Novel bicyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them

ABSTRACT

A method for preventing or treating complications of diabetes by administering a compound of formula (I)  
                 
 
     its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates.

FIELD OF THE INVENTION

[0001] The present invention relates to novel antitobesity andhypocholesterolemic compounds, their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates and pharmaceutically acceptable compositions containing them.More particularly, the present invention relates to novelβ-aryle-α-oxysubstituted alkylcarboxylic acids of the general formulae(I), their derivatives, their analogs, their tautomeric forms, theirstereoisomers, their polymorphs, their pharmaceutically acceptablesalts, their pharmaceutically acceptable solvates and pharmaceuticallyacceptable compositions containing them.

[0002] The present invention also relates to a process for thepreparation of the above said novel compounds, their analogs, theirderivatives, their tautomeric forms, their stereoisomers,. theirpolymorphs, their pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, novel intermediates and pharmaceutical compositionscontaining them.

[0003] The compounds of the present invention lower total cholesterol(TC); increase high density lipoprotein (HDL) and decrease low densitylipoprotein (LDL), which have a beneficial effect on coronary heartdisease and atherosclerosis.

[0004] The compounds of general formula (I) are useful in reducing bodyweight and for he treatment and/or prophylaxis of diseases such ashypertension, coronary heart disease, atherosclerosis, stroke,peripheral vascular diseases and related disorders. These compounds areuseful for the treatment of familial hypercholesterolemia,hypertriglyceridemia, lowering of atherogenic lipoproteins, VLDL (verylow density lipoprotein) and LDL. The compounds of the present inventioncan be used for the treatment of certain renal diseases includingglomerulonephritis, glomerulosclerosis, nephrotic syndrome, andhypertensive nephrosclerosis. The compounds of general formula (I) arealso useful for the treatment and/or prophylaxis of insulin resistance(type II diabetes), impaired glucose tolerance, dyslipidemia, disordersrelated to syndrome X such as hypertension, obesity, insulin resistance,coronary heart disease, and other cardiovascular disorders. Thesecompounds may also be useful as aldose reductase inhibitors, forimproving cognitive functions in dementia, treating diabeticcomplications, disorders related to endothelial cell activation,psoriasis, polycystic ovarian syndrome (PCOS) and osteoporosis.

BACKGROUND OF INVENTION

[0005] Atherosclerosis and other peripheral vascular diseases are themajor causes affecting the quality of life of millions of people.Therefore, considerable attention has been directed towardsunderstanding the etiology of hypercholesterolemia and hyperlipidemiaand development of effective therapeutic strategies.

[0006] Hypercholesterolemia has been defined as plasma cholesterol levelthat exceeds arbitrarily defined value called “normal” level. Recently,it has been accepted that “ideal” plasma levels of cholesterol are muchbelow the “normal” level of cholesterol in the general population andthe risk of coronary artery disease (CAD) increases as cholesterol levelrises above the “optimum” (or “ideal”) value. There is clearly adefinite cause and effect-relationship between hypercholesterolemia andCAD, particularly for individuals with multiple risk factors. Most ofthe cholesterol is present in the esterified forms with variouslipoproteins such as Low density lipoprotein (LDL), Intermediate densitylipoprotein (IDL), High density lipoprotein (HDL) and partially as Verylow density lipoprotein (VLDL). Studies clearly indicate that there isan inverse correlationship between CAD and atherosclerosis with serumHDL-cholesterol concentrations. (Stampfer et al., N. Engl. J. Med., 325(1991), 373-381) and the risk of CAD increases with increasing levels ofLDL and VLDL.

[0007] In CAD, generally “fatty streaks” in carotid, coronary andcerebral arteries, are found which are primarily free and esterifiedcholesterol. Miller et al., (Br. Med. J., 282 (1981), 1741-1744) haveshown that increase in HDL-particles may decrease the number of sites ofstenosis in coronary arteries of human, and high level ofHDL-cholesterol may protect against the progression of atherosclerosis.Picardo et al., (Arteriosclerosis 6 (1986) 434-441) have shown by invitro experiment that HDL is capable of removing cholesterol from cells.They suggest that HDL may deplete tissues of excess free cholesterol andtransfer them to liver (Macikinnon et al., J. Biol. chem. 261 (1986),2548-2552). Therefore, agents that increase HDL cholesterol would havetherapeutic significance for the treatment of hypercholesterolemia andcoronary heart diseases (CHD).

[0008] Obesity is a disease highly prevalent in affluent societies andin the developing world and is a major cause of morbidity and mortality.It is a state of excess body fat accumulation. The causes of obesity areunclear. It is believed to be of genetic origin or promoted by aninteraction between the genotype and environment. Irrespective of thecause, the result is fat deposition due to imbalance between the energyintake versus energy expenditure. Dieting, exercise and appetitesuppression have been a part of obesity treatment. There is a need forefficient therapy to fight this disease since it may lead to coronaryheart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis,reduced fertility and many other psychological and social problems.

[0009] Diabetes and insulin resistance is yet another disease whichseverely effects the quality of a large population in the world. Insulinresistance is the diminished ability of insulin to exert its biologicalaction across a broad range of concentrations. In insulin resistance,the body secretes abnormally high amounts of insulin to compensate forthis defect; failing which, the plasma glucose concentration inevitablyrises and develops into diabetes. Among the developed countries,diabetes mellitus is a common problem and is associated with a varietyof abnormalities including obesity, hypertension, hyperlipidemia (J.Clin. Invest., (1985) 75 : 809.- 817; N. Engl. J. Med. (1987) 317:350-357 ; J. Clin. Endocrinol. Metab., (1988) 66:580-583; J. Clin.Invest., (1975) 68: 957-969) and other renal complications (See PatentApplication No. WO 95/21608). It is now increasingly being recognizedthat insulin resistance and relative hyperinsulinemia have acontributory role in obesity, hypertension, atherosclerosis and type 2diabetes mellitus. The association of insulin resistance with obesity,hypertension and angina has been described as a syndrome having insulinresistance as the central pathogenic link-Syndrome-X.

[0010] Hyperlipidemia is the primary cause for cardiovascular (CVD) andother peripheral vascular diseases. High risk of CVD is related to thehigher LDL (Low Density Lipoprotein) and VLDL (Very Low DensityLipoprotein) seen in hyperlipidemia. Patients having glucoseintolerance/insulin resistance in addition to hyperlipidemia have higherrisk of CVD. Numerous studies in the past have shown that lowering ofplasma triglycerides and total cholesterol, in particular LDL and VLDLand increasing HDL cholesterol help in preventing cardiovasculardiseases.

[0011] Peroxisome proliferator activated receptors (PPAR) are members ofthe nuclear receptor super family. The gamma (γ) isoform of PPAR (PPARγ)has been implicated in regulating differentiation of adipocytes(Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell,(1995) 83: 803-812), whereas the alpha (α) isoform of PPAR (PPARα)mediates fatty acid oxidation (Trend. Endocrin. Metab., (1993) 4 :291-296) thereby resulting in reduction of circulating free fatty acidin plasma (Current Biol. (1995) 5: 618 621). PPARα agonists have beenfound useful for the treatment of obesity (WO 97/36579). It has beenrecently disclosed that there exists synergism for the molecules, whichare agonists for both PPARα and PPARγ and suggested to be useful for thetreatment of syndrome X (WO 97/25042). Similar synergism between theinsulin sensitizer (PPARγ agonist) and HMG CoA reductase inhibitor hasbeen observed which may be useful for the treatment of atherosclerosisand xanthoma. (EP 0 753 298).

[0012] A few β-aryl-α-hydroxy propionic acids their derivatives andtheir analogs have been reported to be useful in the treatment ofhyperglycemia and hypercholesterolemia. Some of such compounds describedin the prior art are outlined below:

[0013] i) U.S. Pat. No. 5,306,726; WO 91/19702 disclose several3-aryl-2-hydroxypropionic acid derivatives of general formulas (IIa) and(IIb) as hypolipidemic and hypoglycemic agents.

[0014] Examples of these compounds are shown in formulas (IIc) and (IId)

[0015] ii) International Patent Applications, WO 95/03038 and WO96/04260 disclose compounds of formula (IIe)

[0016] wherein R^(a) represents 2- benzoxazolyl or 2-pyridyl and R^(b)represent CF₃, CH₂OCH₃ or CH₃. A typical example is(S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoicacid (IIf).

[0017] iii) International Patent Application Nos. WO 94/13650, WO94/01420 and WO 95/17394 disclose the compounds of general formula (IIg)

A¹-X-(CH₂)_(n)—O-A²-A³-Y. R²  (II g)

[0018] wherein A¹ represents aromatic heterocycle, A² representssubstituted benzene ring and A³ represents a moiety of formula(CH₂)_(m)-CH-(OR¹), wherein R¹ represents alkyl groups, m is an integer;X represents substituted or unsubstituted N; Y represents C═O or C═S; R²represents OR³ where R³ may be alkyl, aralklyl, or aryl group; nrepresents an integer in the range of 2-6. An example of these compoundsis shown in formula (IIh)

SUMMARY OF THE INVENTION

[0019] With an objective to develop novel compounds for loweringcholesterol and reducing body weight with beneficial effects in thetreatment and/or prophylaxis of diseases related to increased levels oflipids, atherosclerosis, coronary artery diseases, Syndrome-X, impairedglucose tolerance, insulin resistance, insulin resistance leading totype 2 diabetes and diabetes complications thereof, for the treatment ofdiseases wherein insulin resistance is the pathophysiological mechanism,for the treatment of hypertension, atherosclerosis and coronary arterydiseases with better efficacy, potency and lower toxicity, we focussedour research to develop new compounds effective in the treatment of theabove mentioned diseases. Effort in this direction has led to compoundshaving general formula (I).

[0020] The main objective of the present invention is therefore, toprovide novel β-aryl-α-oxysubstituted alkylcarboxylic acids, theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their pharrnaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutical compositionscontaining them, or their mixtures.

[0021] Another objective of the present invention is to provide novelγ-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives, theiranalogs, their tautomeric forms, their stercoisomers, their polymorphs,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates and pharmaceutical compositions containing them ortheir mixtures which may have agonist activity against PPARα and/orPPARγ, and optionally inhibit HMG CoA reductase, in addition to agonistactivity against PPARα and/or PPARγ.

[0022] Another objective of the present invention is to provide novelβ-aryl-α-oxysubstituted alkylcarboxylic acids, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates and pharmaceutical compositions containing them ortheir mixtures having enhanced activities, without toxic effect or withreduced toxic effect.

[0023] Yet another objective of the present invention is a process forthe preparation of novel β-aryl-α-oxysubstituted alkylcarboxylic acidsof formula (I), their derivatives, their analogs, their tautomericforms, their stereoisomers, their polymorphs, their pharmaceuticallyacceptable salts and their pharmaceutically acceptable solvates.

[0024] Still another objective of the present invention is to providepharmaceutical compositions containing compounds of the general formula(I), their analogs, their derivatives, their tautomers, theirstereoisomers, their polymorphs, their salts, solvates or their mixturesin combination with suitable carriers, solvents, diluents and othermedia normally employed in preparing such compositions.

[0025] Another objective of the present invention is to provide novelintermediates, a process for their preparation and use of theintermediates in processes for preparation of β-aryl-α-oxysubstitutedalkyl carboxylic acids of formula (I), their derivatives, their analogs,their tautomers, their stereoisomers, their polymorphs, their salts andtheir pharmaceutically acceptable solvates.

DETAILED DESCRIPTION OF THE INVENTION

[0026] α-Oxysubstituted propionic acids, their derivatives and theiranalogs of the present invention have the general formula (I)

[0027] where the groups R¹, R², R³, R⁴, and the groups R⁵ and R⁶ whenattached to a carbon atom, may be same or different and representhydrogen, halogen, hydroxy, nitro, cyano, formyl or optionallysubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;one or both of R⁵ and R⁶ may also represent an oxo group when they areattached to a carbon atom; R⁵ and R⁶ when attached to a nitrogen atomrepresents hydrogen, hydroxy, formyl or optionally substituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl,amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl,aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,or sulfonic acid derivatives; X represents a heteroatom selected fromoxygen, sulfur or NR¹¹ where R¹¹ is selected from hydrogen or optionallysubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Arrepresents an optionally substituted divalent single or fused aromaticor heterocyclic group; R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, optionally substituted aralkyl group or forms abond together with the adjacent group R⁸; R⁸ represents hydrogen,hydroxy, alkoxy, halogen, lower alkyl group, acyl, or optionallysubstituted aralkyl or R⁸ forms a bond together with R⁷; R⁹ representshydrogen, or optionally substituted groups selected from alkyl,cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,or heteroaralkyl groups; R¹⁰ represents hydrogen or optionallysubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl, or heteroaralkyl groups; Y represents oxygenor NR¹², where R¹² represents hydrogen, alkyl, aryl, hydroxyalkyl,aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R¹⁰ and R¹²together may form a 5 or 6 membered cyclic structure containing carbonatoms, which may optionally contain one or more heteroatoms selectedfrom oxygen, sulfur or nitrogen; the linking group represented by-(CH₂)_(n)-(O)_(m)- may be attached either through a nitrogen atom or acarbon atom; n is an integer ranging from 1-4 and m is an integer 0 or1.

[0028] Suitable groups represented by R¹- R⁴ and the groups R⁵ and R⁶when attached to carbon atom, may be selected from hydrogen, halogenatom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano,nitro, formyl; substituted or unsubstituted (C₁—C₁₂)alkyl group,especially, linear or branched (C₁—C₆)alkyl group, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, n-pentyl,isopentyl, hexyl and the like; cyclo(C₃—C₆)alkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, thecycloalkyl group may be substituted; cyclo(C₃—C₆)alkoxy group such ascyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and thelike, the cycloalkoxy group may be substituted; aryl group such asphenyl or naphthyl, the aryl group may be substituted; aralkyl such asbenzyl or phenethyl, C₆H₅CH₂CH₂CH₂, naphthylmethyl and the like, thearalkyl group may be substituted and the substituted aralkyl is a groupsuch as CH₃C₆H₄CH₂, Hal-C₆H₄CH₂, CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂ and thelike; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl,benzofuranyl and the like, the heteroaryl group may be substituted;heterocyclyl groups such as aziridinyl, pyrrolidinyl, morpholinyl,piperidinyl, piperazinyl and the like, the heterocyclyl group may besubstituted; aralkoxy group such as benzyloxy, phenethyloxy,naphthylmethyloxy, phenylpropyloxy and the like, the aralkoxy group maybe substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl,oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may besubstituted; aralkylamino group such as C₆H₅CH₂NH, C₆H₅CH₂CH₂NH,C₆H₅CH₂NCH₃ and the like, which may be substituted; alkoxycarbonyl suchas methoxycarbonyl, ethoxycarbonyl and the like, which may besubstituted; aryloxycarbonyl group such as optionally substitutedphenoxycarbonyl, naphthyloxycarbonyl and the like; aralkoxycarbonylgroup such as benzyloxycarbonyl, phenethyloxycarbonyl,naphthylmethoxycarbonyl and the like, which may be substituted;(C₁—C₆)alkylamino group such as NHCH₃, NHC₂H₅, NHC₃H₇, NHC₆Hl₃, and thelike, which may be substituted; (C₁—C₆)dialkylamino group such asN(CH₃)₂, NCH₃(C₂H₅), N(C₂H₅)₂ and the like, which may be substituted;alkoxyalkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl,ethoxyethyl and the like, which may be substituted; aryloxyalkyl groupsuch as C₆H₅OCH₂, C₆H₅OCH₂CH₂, naphthyloxymethyl and the like, which maybe substituted; aralkoxyalkyl group such as C₆H₅CH₂OCH₂, C₆H₅CH₂OCH₂CH₂and the like, which may be substituted; heteroaryloxy andheteroaralkoxy, wherein heteroaryl moiety is as defined earlier and maybe substituted; aryloxy group such as phenoxy, naphthyloxy and the like,the aryloxy group may be substituted; arylamino group such as HNC₆H₅,NCH₃(C₆H₅), NHC₆H₄CH₃, NHC₆H₄-Hal and the like, which may besubstituted; amino group which may be substituted; amino(C₁—C₆)alkylwhich may be substituted; hydroxy(C₁—C₆)alkyl which may be substituted;(C₁—C₆)alkoxy such as methoxy, ethoxy, propyloxy, butyloxy,iso-propyloxy and the like, which may be substituted; thio(C₁—C₆)alkylwhich may be substituted; (C₁—C₆)alkylthio which may be substituted;acyl group such as acetyl, propionyl or benzoyl and the like, the acylgroup may be substituted; acylamino groups such as NHCOCH₃, NHCOC₂H₅,NHCOC₃H₇, NHCOC₆H₅ and the like, which may be substituted;aralkoxycarbonylamino group such as NHCOOCH₂C₆H₅, NHCOOCH₂CH₂C₆H₅,N(CH₃)COOCH₂C₆H₅, N(C₂H₅)COOCH₂C₆H₅, NHCOOCH₂C₆H₄CH₃, NHCOOCH₂C₆H₄OCH₃and the like, which may be substituted; aryloxycarbonylamino group suchas NHCOOC₆H₅, NHCOOC₆H₅, NCH₃COOC₆H₅, NC₂H₅COOC₆H₅, NHCOOC₆H₄CH₃,NHCOOC₆H₄OCH₃ and the like, which may be substituted;alkoxycarbonylamino group such as NHCOOC₂H₅, NHCOOCH₃ and the like,which may be substituted; carboxylic acid or its derivatives such asamides, like CONH₂, CONHMe, CONMe₂, CONHEt, CONEt₂, CONHPh and the like,the carboxylic acid derivatives may be substituted; acyloxy group suchas OOCMe, OOCEt, OOCPh and the like, which may be substituted; sulfonicacid or its derivatives such as SO₂NH₂, SO₂NHMe, SO₂NMe₂, SO₂NHCF₃ andthe like, the sulfonic acid derivatives may be substituted. One or bothof R⁵ and R⁶ may also represent an oxo group.

[0029] When the groups represented by R¹- R⁴ and the groups R⁵ and R⁶when attached to carbon atom are substituted, the substituents may beselected from halogen, hydroxy, or nitro or optionally substitutedgroups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aralkoxy,aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl,acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl,aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkylgroups, carboxylic acid or its derivatives, or sulfonic acid or itsderivatives .

[0030] It is preferred that the substituents on R¹- R⁶ represent halogenatom such as fluorine, chlorine, bromine; alkyl group such as methyl,ethyl, isopropyl, n-propyl, n-butyl; cycloalkyl group such ascyclopropyl; aryl group such as phenyl; aralkyl group such as benzyl;(C₁—C₃)alkoxy, benzyloxy, hydroxy group, acyl or acyloxy groups.

[0031] Suitable R⁵ and R⁶ when attached to nitrogen atom is selectedfrom hydrogen, hydroxy, formyl; substituted or unsubstituted(C₁—C₁₂)alkyl group, especially, linear or branched (C₁—C₆)alkyl group,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl,n-pentyl, isopentyl, hexyl and the like; cyclo(C₃—C₆)alkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, thecycloalkyl group may be substituted; cyclo(C₃—C₆)alkyloxy group such ascyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and thelike, the cycloalkoxy group may be substituted; aryl group such asphenyl, naphthyl and the like, the aryl group may be substituted;aralkyl such as benzyl or phenethyl, C₆H₅CH₂CH₂CH₂, naphthylmethyl andthe like, the aralkyl group may be substituted and the substitutedaralkyl is a group such as CH₃C₆H₄CH₂, Hal-C₆H₄CH₂, CH₃OC₆H₄CH₂,CH₃OC₆H₄CH₂CH₂ and the like; heteroaryl group such as pyridyl, thienyl,furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl,tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroarylgroup may be substituted; heterocyclyl groups such as aziridinyl,pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and the like, theheterocyclyl group may be substituted; aralkoxy group such as benzyloxy,phenethyloxy, naphthylmethyloxy, phenylpropyloxy and the like, thearalkoxy group may be substituted; heteroaralkyl group such asfuranmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like,the heteroaralkyl group may be substituted; aralkylamino group such asC₆H₅CH₂NH, C₆H₅CH₂CH₂NH, C₆H₅CH₂NCH₃ and the like, which may besubstituted; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl andthe like, which may be substituted; aryloxycarbonyl group such asoptionally substituted phenoxycarbonyl, naphthyloxycarbonyl and thelike; aralkoxycarbonyl group such as benzyloxycarbonyl,phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may besubstituted; (C₁—C₆)alkylamino group such as NHCH₃, N(CH₃)₂, NCH₃(C₂H₅),NHC₂H₅, NHC₃H₇, NHC₆H₁₃ and the like, which may be substituted;alkoxyalkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl,ethoxyethyl and the like, which may be substituted; aryloxyalkyl groupsuch as C₆H₅OCH₂, C₆H₅OCH₂CH₂, naphthyloxymethyl and the like, which maybe substituted; aralkoxyalkyl group such as C₆H₅CH₂OCH₂, C₆H₅CH₂OCH₂CH₂and the like, which may be substituted; heteroaryloxy andheteroaralkoxy, wherein heteroaryl moiety is as defined earlier and maybe substituted; aryloxy group such as phenoxy, naphthyloxy and the like,the aryloxy group may be substituted; arylamino group such as HNC₆H₅,NCH₃(C₆H₅), NHC₆H₄CH₃, NHC₆H₄-Hal and the like, which may besubstituted; amino group which may be substituted; amino(C₁—C₆)alkylwhich may be substituted; hydroxy(C₁—C₆)alkyl which may be substituted;(C₁—C₆)alkoxy such as methoxy, ethoxy, propyloxy, butyloxy,iso-propyloxy and the like, which may be substituted; thio(C₁—C₆)alkylwhich may be substituted; (C₁—C₆)alkylthio which may be substituted;acyl group such as acetyl, propionyl, benzoyl and the like, the acylgroup may be substituted; acylamino groups such as NHCOCH₃, NHCOC₂H₅,NHCOC₃H₇, NHCOC₆H₅ and the like, which may be substituted; carboxylicacid derivatives such as amides, like CONH₂, CONHMe, CONMe₂, CONHEt,CONEt₂, CONHPh and the like, the carboxylic acid derivatives may besubstituted; acyloxy group such as OOCMe, OOCEt, OOCPh and the like,which may be substituted; sulfonic acid derivatives such as SO₂NH₂,SO₂NHMe, SO₂NMe₂, SO₂NHCF₃ and the like, the sulfonic acid derivativesmay be substituted.

[0032] When the groups represented by R⁵ and R⁶ attached to nitrogen aresubstituted, preferred substituents may be selected from halogen such asfluorine, chlorine; hydroxy, acyl, acyloxy, or amino groups.

[0033] Suitable X includes oxygen, sulfur or a group NR¹¹ as definedabove, preferably oxygen and sulfur. Suitably R¹¹ represent hydrogen,(C₁—C₆)alkyl, (C₃—C₆)cycloalkyl, aryl group such as phenyl or naphthyl,aralkyl group such as benzyl or phenethyl; acyl group such as acetyl,propanoyl, butyroyl, benzoyl and the like; (C₁—C₆)alkoxycarbonyl;aryloxycarbonyl such as phenoxycarbonyl, CH₃OC₆HOCO, Hal-C₆H₄OCO,CH₃C₆H₄OCO, naphthyloxycarbonyl and the like; aralkoxycarbonyl such asbenzyloxycarbonyl, phenethyloxycarbonyl and the like; the groupsrepresented by R¹¹ may be substituted or unsubstituted. When the groupsrepresented by R¹¹ are substituted, the substituents may be selectedfrom halogen, optionally halogenated lower alkyl, hydroxy, andoptionally halogenated (C₁—C₃)alkoxy groups.

[0034] It is preferred that the group represented by Ar be substitutedor unsubstituted groups selected from divalent phenylene, naphthylene,pyridyl, quinolinyl, benzofuranyl, dihydrobenzofuryl, benzopyranyl,dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl,pyrazolyl, benzothiazolyl, benzoxazolyl and the like. The substituentson the group represented by Ar may be selected from linear or branchedoptionally halogenated (C₁—C₆)alkyl, optionally halogenated(C₁—C₃)alkoxy, halogen, acyl, amino, acylamino, thio or carboxylic orsulfonic acids and their derivatives.

[0035] It is more preferred that Ar represents a substituted orunsubstituted divalent, phenylene, naphthylene, benzofuranyl, indolyl,indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl orbenzoxazolyl groups.

[0036] It is still more preferred that Ar is represented by divalentphenylene or benzofuranyl, which may be optionally substituted bymethyl, halomethyl, methoxy or halomethoxy groups.

[0037] Suitable R⁷ includes hydrogen, lower alkyl groups such as methyl,ethyl or propyl; hydroxy, (C₁—C₃)alkoxy; halogen atom such as fluorine,chlorine, bromine, iodine; aralkyl such as benzyl, phenethyl, which maybe optionally substituted or R⁷ together with R⁸ represents a bond.

[0038] Suitable R⁸ may be hydrogen, lower alkyl groups such as methyl,ethyl or propyl; hydroxy, (C₁—C₃)alkoxy; halogen atom such as fluorine,chlorine, bromine, iodine; acyl group such as linear or branched(C₂—C₁₀)acyl group such as acetyl, propanoyl, butanoyl, pentanoyl,benzoyl and the like; aralkyl such as benzyl, phenethyl, which may beoptionally substituted or together with R⁷ forms a bond.

[0039] Suitable groups represented by R⁹ may be selected from hydrogen,linear or branched (C₁—C₁₆)alkyl, preferably (C₁—C₁₂)alkyl group such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl,octyl and the like; (C₃—C₇)cycloalkyl group such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like, the cycloalkyl groupmay be substituted; aryl group such as phenyl, naphthyl, the aryl groupmay be substituted; heteroaryl group such as pyridyl, thienyl, furyl andthe like, the heteroaryl group may be substituted; heteroaralkyl groupsuch as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and thelike, the heteroaralkyl group may be substituted; aralkyl group such asbenzyl and phenethyl and the like, wherein the alkyl moiety may containC₁—C₆ atoms, wherein the aryl moiety may be substituted; heterocyclylgroup such as aziridinyl, pyrrolidinyl, piperidinyl and the like, theheterocyclyl group may be substituted; (C₁—C₆)alkoxy(C₁—C₆)alkyl groupsuch as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropyl and thelike, the alkoxyalkyl group may be substituted; linear or branched(C₂—C₁₆)acyl group such as acetyl, propanoyl, butanoyl, benzoyl,octanoyl, decanoyl and the like, which may be substituted;(C₁—C₆)alkoxycarbonyl, the alkyl group may be substituted;aryloxycarbonyl such as phenoxycarbonyl, naphthyloxycarbonyl and thelike, the aryl group may be substituted; (C₁—C₆)alkylaminocarbonyl, thealkyl group may be substituted; arylaminocarbonyl such as PhNHCO,naphthylaminocarbonyl and the like, the aryl moiety may be substituted.The substituents may be selected from halogen, hydroxy, or nitro oroptionally substituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl,heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino,aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio,thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acidor its derivatives .

[0040] Suitable groups represented by R¹⁰ may be selected from hydrogen,linear or branched (C₁—C₁₆)alkyl, preferably (C₁—C₁₂)alkyl group such asmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl,octyl and the like; (C₃—C₇)cycloalkyl such as cyclopropyl, cyclopentyl,cyclohexyl and the like, the cycloalkyl group may be substituted; arylgroup such as phenyl, naphthyl and the like, the aryl group may besubstituted; heteroaryl group such as pyridyl, thienyl, furyl and thelike, the heteroaryl group may be substituted; heteroaralkyl group suchas furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like,the heteroaralkyl group may be substituted; aralkyl group such as benzyland phenethyl and the like, the aralkyl group may be substituted; andheterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and thelike, the heterocyclyl group may be substituted. The substituents on R¹⁰may be selected from the same group of R¹-R⁶.

[0041] Suitable groups represented by R¹² may be selected from hydrogen,linear or branched (C₁—C₁₆)alkyl, preferably (C₁—C₁₂)alkyl;hydroxy(C₁—C₆)alkyl; aryl group such as phenyl, naphthyl and the like;aralkyl group such as benzyl, phenethyl and the like; heterocyclyl groupsuch as aziridinyl, pyrrolidinyl, piperidinyl, and the like; heteroarylgroup such as pyridyl, thienyl, furyl and the like; and heteroaralkylgroup such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyland the like.

[0042] Suitable ring structures formed by R¹⁰ and R¹² together may beselected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl andthe like.

[0043] Suitable m is an integer ranging from 0-1. It is preferred thatwhen m=0, Ar represents a divalent benzofuranyl, benzoxazolyl,benzothiazolyl, indolyl, indolinyl, dihydrobenzofuryl, ordihydrobenzopyranyl group and when m=1, Ar represents a substituted orunsubstituted groups selected from divalent phenylene, naphthylene,pyridyl, quinolinyl, benzofuranyl, dihydrobenzofuryl, benzopyranyl,dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl,pyrazolyl, benzothiazolyl, benzoxazolyl and the like.

[0044] Suitable n is an integer ranging from 1 to 4, preferably nrepresents an integer 1 or 2.

[0045] It is preferred that when m=1, n represents 2.

[0046] It is also preferred that when m=0, n represents 1.

[0047] Pharmaceutically acceptable salts forming part of this inventioninclude salts of the carboxylic acid moiety such as alkali metal saltslike Li, Na, and K salts, alkaline earth metal salts like Ca and Mgsalts, salts of organic bases such as lysine, arginine, guanidine,diethanolamine, choline and the like, ammonium or substituted ammoniumsalts, and aluminum salts. Salts may include acid addition salts whereappropriate which are, sulphates, nitrates, phosphates, perchlorates,borates, hydrohalides, acetates, tartrates, maleates, citrates,succinates, palmoates, methanesulphonates, benzoates, salicylates,hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates,ketoglutarates and the like. Pharmaceutically acceptable solvates may behydrates or comprising other solvents of crystallization such asalcohols.

[0048] Particularly useful compounds according to the present inventioninclude:

[0049] Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;

[0050] (±) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0051] (+) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0052] (−) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0053] Ethyl(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate;

[0054] Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;

[0055] (±) Methyl3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate;

[0056] (+) Methyl3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate;

[0057] (−) Methyl3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate;

[0058] (±)Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0059] (+)Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0060] (−)Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0061] (±) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0062] (+) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0063] (−) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0064] (±) Methyl2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0065] (+) Methyl2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0066] (−) Methyl2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0067] Ethyl(E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;

[0068] (±) Methyl3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0069] (+) Methyl3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0070] (−) Methyl3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0071] Ethyl(E/Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropenoate;

[0072] (±) Methyl3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate;

[0073] (+) Methyl3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate;

[0074] (−) Methyl3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate;

[0075] Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;

[0076] Ethyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;

[0077] Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate;

[0078] Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate;

[0079] Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoate;

[0080] Ethyl (E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate;

[0081] (±) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0082] (+) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0083] (−) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0084] Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate;

[0085] (±) Methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0086] (+) Methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0087] (−) Methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0088] Ethyl(E/Z)-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate;

[0089] (±) Methyl3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;

[0090] (+) Methyl3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;

[0091] (−) Methyl3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;

[0092] Ethyl(E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate;

[0093] (±) Methyl3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;

[0094] (+) Methyl3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;

[0095] (−) Methyl3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;

[0096] (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0097] (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0098] (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0099] (±)3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts;

[0100] (+)3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts;

[0101] (−)3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts;

[0102] (±)3-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts;

[0103] (+)3-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts;

[0104] (−)3-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts;

[0105] (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0106] (+)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0107] (−)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0108] (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0109] (+)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0110] (−)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0111] (±)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0112] (+)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0113] (−)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0114] (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0115] (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0116] (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0117] (±)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0118] (+)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0119] (−)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0120] (±)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0121] (+)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0122] (−)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0123] (±)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0124] (+)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0125] (−)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;

[0126]2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0127]2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0128] (±)3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0129] (+)3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0130] (−)3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0131] (±)3-[4-[2-(3-Oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0132] (+)3-[4-[2-(3-Oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0133] (−)3-[4-[2-(3-Oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;

[0134] (±)3-[6-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts;

[0135] (+)3-[6-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts;

[0136] (−)3-[6-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts;

[0137] (±)3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts;

[0138] (+)3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts;

[0139] (−)3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts;

[0140] (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts;

[0141] (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts;

[0142] (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts;

[0143] (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts;

[0144] (+)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts;

[0145] (−)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts;

[0146] (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoicacid and its salts;

[0147] (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoicacid and its salts;

[0148] (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoicacid and its salts;

[0149] (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid and its salts;

[0150] (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid and its salts;

[0151] (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid and its salts;

[0152] (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid and its salts;

[0153] (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid and its salts;

[0154] (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid and its salts;

[0155] (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0156] (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0157] (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0158] (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0159] (+)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0160] (−)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0161] (±) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0162] (+) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0163] Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0164] (±)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0165] (+)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0166] (−)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0167] (±) Methyl 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0168] (+) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0169] (−) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;

[0170] (±)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0171] (+)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0172] (−)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts;

[0173] (±) 4-Nitrophenyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0174] (+) 4-Nitrophenyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0175] (−) 4-Nitrophenyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;

[0176] (±) 3-[4-(4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoic acid and its salts;

[0177] (+)3-[4-(4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoicacid and its salts;

[0178] (−)3-[4-(4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoicacid and- its salts;

[0179] (±)4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;

[0180] (+)4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;and

[0181] (−)4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate.

[0182] According to a feature of the present invention, the compound ofgeneral formula (I) where R⁷ and R⁸ together represent a bond, Yrepresents oxygen atom, R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, X, n, m and Arare as defined earlier, can be prepared by any of the following routesshown in Scheme I.

Route (1)

[0183] The reaction of a compound of the general formula (IIIa) whereall symbols are as defined earlier with a compound of formula (IIIb)where R⁹, R¹⁰ are as defined earlier and R¹⁴ represents (C₁—C₆)alkyl, toyield compound of general formula (I) where R⁷, R⁸ together represent abond and Y represents an oxygen atom may be carried out neat in thepresence of a base such as alkali metal hydrides like NaH, or KH ororganolithiums like CH₃Li, BuLi and the like or alkoxides such as NaOMe,NaOEt, K⁺BuO⁻or mixtures thereof. The reaction may be carried out in thepresence of solvents such as THF, dioxane, DMF, DMSO, DME and the likeor mixtures thereof. HMPA may be used as cosolvent. The reactiontemperature may range from −78° C. to 50° C., preferably at atemperature in the range of −10° C. to 30° C. The reaction is moreeffective under anhydrous conditions. The compound of general formula(IIIb) may be prepared according to the procedure described in theliterature (Annalen. Chemie, (1996) 53, 699).

Route (2)

[0184] The reaction of a compound of general formula (IIIc) where allsymbols are as defined earlier with a compound of general formula (IIId)where R⁷, R⁸ together represent a bond and all symbols are as definedearlier and L¹ is a leaving group such as halogen atom,p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and thelike, preferably a halogen atom to produce a compound of general formula(I) defined above may be carried out in the presence of solvents such asDMSO, DMF, DME, THF, dioxane, ether and the like or a combinationthereof. The reaction may be carried out in an inert atmosphere whichmay be maintained by using inert gases such as N₂, Ar, or He. Thereaction may be effected in the presence of a base such as alkalis likesodium hydroxide, or potassium hydroxide; alkali metal carbonates likesodium carbonate, or potassium carbonate; alkali metal hydrides such assodium hydride or potassium hydride; organometallic bases like n-butyllithium; alkali metal amides like sodamide or mixtures thereof. Theamount of base may range from 1 to 5 equivalents, based on the amount ofthe compound of formula (IIIc), preferably the amount of base rangesfrom 1 to 3 equivalents. Phase transfer catalysts such astetraalkylammonium halide or hydroxide may be added. The reaction may becarried out at a temperature in the range of 0° C. to 150° C.,preferably at a temperature in the range of 15° C. to 100° C. Theduration of the reaction may range from 0.25 to 48 hours, preferablyfrom 0.25 to 12 hours.

Route (3)

[0185] The reaction of a compound of formula (IIIe) where all symbolsare as defined earlier with a compound of formula (IIIf) where R⁹=R¹⁰and are as defined earlier, to produce a compound of the formula (I)where R⁷ and R⁸ together represent a bond may be carried out neat in thepresence of a base such as alkali metal hydrides like NaH, KH ororganolithiums like CH₃Li, BuLi and the like or alkoxides such as NaOMe,NaOEt, K⁺BuO⁻ and the like or mixtures thereof. The reaction may becarried out in the presence of aprotic solvents such as THF, dioxane,DMF, DMSO, DME and the like or mixtures thereof. HMPA may be used ascosolvent. The reaction temperature may range from −78° C. to 100° C.,preferably at a temperature in the range of −10° C. to 50° C.

Route (4)

[0186] The reaction of a compound of the general formula (IIIa) whereall other symbols are as defined earlier, with a compound of formula(IIIg) where R⁸ represents hydrogen atom, R⁹ and R¹⁰ are as definedearlier may be carried out in the presence of a base. The nature of thebase is not critical. Any base normally employed for aldol condensationreaction may be employed; bases like metal hydride such as NaH, or KH,metal alkoxides such as NaOMe, K⁺BuO⁻, or NaOEt, metal amides such asLiNH₂, or LiN(ipr)₂ may be used. Aprotic solvent such as THF, ether, ordioxane may be used. The reaction may be carried out in an inertatmosphere which may be maintained by using inert gases such as N₂, Ar,or He and the reaction is more effective under anhydrous conditions.Temperature in the range of −80° C. to 35° C. may be used. The β-hydroxyproduct initially produced may be dehydrated under conventionaldehydration conditions such as treating with PTSA in solvents such asbenzene or toluene. The nature of solvent and dehydrating agent is notcritical. Temperature in the range of 20° C. to reflux temperature ofthe solvent used may be employed, preferably at reflux temperature ofthe solvent by continuous removal of water using a Dean Stark waterseparator.

Route (5)

[0187] The reaction of compound of formula (IIIh) where all symbols areas defined earlier and L¹ represents a leaving group such as as halogenatom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonateand the like with a compound of formula (IIIi) where R⁷ and R⁸ togetherrepresent a bond and R⁹, R¹⁰ and Ar are as defined earlier to produce acompound of the formula (I) where m=1 and all other symbols are asdefined above may be carried out in the presence of aprotic solventssuch as THF, DMF, DMSO, DME and the like or mixtures thereof. Thereaction may be carried out in an inert atmosphere which may bemaintained by using inert gases such as N₂, Ar, or He. The reaction maybe effected in the presence of a base such as K₂CO₃, Na₂CO₃ or NaH ormixtures thereof. Acetone may be used as solvent when Na₂CO₃ or K₂CO₃ isused as a base. The reaction temperature may range from 0° C.-120° C.,preferably at a temperature in the range of 30° C.-100° C. The durationof the reaction may range from 1 to 24 hours, preferably from 2 to 12hours. The compound of formula (IIIi) can be prepared according to knownprocedures by a Wittig Homer reaction between the hydroxy protected arylaldehyde such as benzyloxyaryl aldehyde and compound of formula (IIIb),followed by deprotection.

Route (6)

[0188] The reaction of compound of general formula (IIIj) where allsymbols are as defined earlier with a compound of general formula (IIIi)where R⁷ and R⁸ together represent a bond and R⁹, R¹⁰ and Ar are asdefined earlier to produce a compound of the formula (I) where m=1 andall other symbols are as defined above may be carried out using suitablecoupling agents such as dicyclohexyl urea,triarylphosphine/dialkylazadicarboxylate such as PPh₃/DEAD and the like.The reaction may be carried out in the presence of solvents such as THF,DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile, carbontetrachloride and thelike. The inert atmosphere may be maintained by using inert gases suchas N₂, Ar, or He. The reaction may be effected in the presence of DMAP,HOBT and they may be used in the range of 0.05 to 2 equivalents,preferably 0.25 to 1 equivalents. The reaction temperature may be in therange of 0° C. to 100° C., preferably at a temperature in the range of20° C. to 80° C. The duration of the reaction may range from 0.5 to 24hours, preferably from 6 to 12 hours.

[0189] In yet another embodiment of the present invention, the compoundof the general formula (I) where R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, X, n,m, R⁷ represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl,optionally substituted aralkyl group, R⁸ represents hydrogen, hydroxy,alkoxy, halogen, lower alkyl group, acyl or optionally substitutedaralkyl and Ar are as defined earlier and Y represents oxygen can beprepared by one or more of the processes shown in Scheme - II:

Route 7

[0190] The reduction of compound of the formula (IVa) which represents acompound of formula (I) where R⁷ and R⁸ together represent a bond and Yrepresents an oxygen atom and all other symbols are as defined earlier,obtained as described earlier (Scheme-I), to yield a compound of thegeneral formula (I) where R⁷ and R⁸ each represent a hydrogen atom andall symbols are as defined earlier, may be carried out in the presenceof gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, and thelike. Mixtures of catalysts may be used. The reaction may also beconducted in the presence of solvents such as dioxane, acetic acid,ethyl acetate and the like. A pressure between atmospheric pressure and80 psi may be employed. The catalyst may be preferably 5-10% Pd/C andthe amount of catalyst used may range from 50-300% w/w. The reaction mayalso be carried out by employing metal solvent reduction such asmagnesium in alcohol or sodium amalgam in alcohol, preferably methanol.The hydrogenation may be carried out in the presence of metal catalystscontaining chiral ligands to obtain a compound of formula (I) inoptically active form. The metal catalyst may contain rhodium,ruthenium, indium and the like. The chiral ligands may preferably bechiral phosphines such as (2S,3S)-bis(diphenylphosphino)butane,1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane,(−)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butaneand the like. Any suitable chiral catalyst may be employed which wouldgive required optical purity of the product (I) (Ref: Principles ofAsymmetric Synthesis, Tet. Org. Chem. Series Vol 14, pp311-316, Ed.Baldwin J. E.).

Route 8

[0191] The reaction of compound of formula (IVb) where all symbols areas defined earlier and L² is a leaving group such as halogen atom withan alcohol of general formula (IVc), where R⁹ is as defined earlier toproduce a compound of the formula (I) defined earlier may be carried outin the presence of solvents such as THF, DMF, DMSO, DME and the like ormixtures thereof The reaction may be carried out in an inert atmospherewhich may be maintained by using inert gases such as N₂, Ar, or He. Thereaction may be effected in the presence of a base such as KOH, NaOH,NaOMe, NaOEt, K⁺BuO⁻ or NaH or mixtures thereof. Phase transfercatalysts such as tetraalkylammonium halides or hydroxides may beemployed. The reaction temperature may range from 20° C.-120° C.,preferably at a temperature in the range of 30° C.-100° C. The durationof the reaction may range from 1 to 12 hours, preferably from 2 to 6hours. The compound of general formula (IVb) and its preparation hasbeen disclosed in the copending U.S. application Ser. No. 08/982,910.

Route 9

[0192] The reaction of compound of formula (IIIh) defined earlier withcompound of formula (IIIi) where all symbols are as defined earlier toproduce a compound of the formula (I) where m=1 and all other symbolsare as defined above, may be carried out in the presence of solventssuch as THF, DMF, DMSO, DME and the like or mixtures thereof. Thereaction may be carried out in an inert atmosphere which is maintainedby using inert gases such as N₂, Ar or He. The reaction may be effectedin the presence of a base such as K₂CO₃, Na₂CO₃, NaH or mixturesthereof. Acetone may be used as a solvent when K₂CO₃ or Na₂CO₃ is usedas a base. The reaction temperature may range from 20° C.-120° C.,preferably at a temperature in the range of 30° C.-80° C. The durationof the reaction may range from 1 to 24 hours, preferably from 2 to 12hours. The compound of formula (IIIi) may be prepared by Wittig Homerreaction between the protected hydroxyaryl aldehyde and compound offormula (IIIb) followed by reduction of the double bond anddeprotection. Alternatively, the compound of formula (IIIi) may beprepared by following a procedure disclosed in WO 94/01420.

Route 10

[0193] The reaction of compound of general formula (IIIj) definedearlier with a compound of general formula (IIIi) where all symbols areas defined earlier to produce a compound of the formula (I) where m=1and all other symbols are as defined above may be carried out usingsuitable coupling agents such as dityclohexyl urea,triarylphosphine/dialkylazadicarboxylate such as PPh₃/DEAD and the like.The reaction may be carried out in the presence of solvents such as THF,DME, CH₂Cl₂, CHCl₃, toluene, acetonitrile, carbon tetrachloride and thelike. The inert atmosphere may be maintained by using inert gases suchas N₂, Ar, or He. The reaction may be effected in the presence of DMAP,HOBT and they may be used in the range of 0.05 to 2 equivalents,preferably 0.25 to 1 equivalents. The reaction temperature may be in therange of 0° C. to 100° C., preferably at a temperature in the range of20° C. to 80° C. The duration of the reaction may range from 0.5 to 24hours, preferably from 6 to 12 hours.

Route 11

[0194] The reaction of compound of formula (IVd) which represents acompound of formula (I) where R⁹ represents hydrogen atom and all othersymbols are as defined earlier with a compound of formula (IVe) where R⁹is as defined earlier and L² is a leaving group such as a halogen atom,may be carried out in the presence of solvents such as THF, DMF, DMSO,DME and the like. The inert atmosphere may be maintained by using inertgases such as N₂, Ar or He. The reaction may be effected in the presenceof a base such as KOH, NaOH, NaOMe, K⁺BuO⁻, NaH and the like. Phasetransfer catalyst such as tetraalkylammonium halides or hydroxides maybe employed. The reaction temperature may range from 20° C. to 150° C.,preferably at a temperature in the range of 30° C. to 100° C. Theduration of the reaction may range from 1 to 24 hours, preferably from 2to 6 hours.

Route 12

[0195] The reaction of a compound of the general formula (IIIa) asdefined above with a compound of formula (IIIg) where R⁸, R⁹, and R¹⁰are as defined earlier may be carried out under conventional conditions.The base is not critical. Any base normally employed for aldolcondensation reaction may be employed, metal hydride such as NaH, or KH;metal alkoxides such as NaOMe, K^(t)BuO⁻, or NaOEt; metal amides such asLiNH₂, or LiN(ipr)₂. Aprotic solvent such as THF may be used. Inertatmosphere may be employed such as argon and the reaction is moreeffective under anhydrous conditions. Temperature in the range of −80°C. to 25° C. may be used. The hydroxy aldol product may bedehydroxylated using conventional methods, conveniently by ionichydrogenation technique such as by treating with a trialkyl silane inthe presence of an acid such as trifluoroacetic acid. Solvent such asCH₂Cl₂ may be used. Favorably, the reaction proceeds at 25° C. A highertemperature may be employed if the reaction is slow.

Route 13

[0196] The reaction of a compound of general formula (IIIc) where allsymbols are as defined earlier with a compound of general formula (IIId)where L¹ is a leaving group such as halogen atom, p-toluenesulfonate,methanesulfonate, trifluoromethanesulfonate and the like, preferably L¹is a halogen atom, and all other symbols are as defined earlier toproduce a compound of general formula (I) may be carried out in thepresence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and thelike or a combination thereof. The reaction may be carried out in aninert atmosphere which may be maintained by using inert gases such asN₂, Ar, or He. The reaction may be effected in the presence of a basesuch as alkalis like sodium hydroxide, or potassium hydroxide, alkalimetal carbonates like sodium carbonate, or potassium carbonate; alkalimetal hydrides such as sodium hydride or potassium hydride;organometallic bases like n-butyl lithium, alkali metal amides likesodamide or mixtures thereof. The amount of base may range from 1 to 5equivalents, based on the amount of the compound of formula (IIIc),preferably the amount of base ranges from 1 to 3 equivalents. Thereaction may be carried out at a temperature in the range of 0° C. to150° C., preferably at a temperature in the range of 15° C. to 100° C.The duration of the reaction may range from 0.25 to 24 hours, preferablyfrom 0.25 to 12 hours.

Route 14

[0197] The conversion of compound of formula (IVf) to a compound offormula (I) may be carried out either in the presence of base or acidand the selection of base or acid is not critical. Any base normallyused for hydrolysis of nitrile to acid may be employed, such as metalhydroxides such as NaOH, or KOH in an aqueous solvent or any acidnormally used for hydrolysis of nitrile to ester may be employed such asdry HCl in an excess of alcohol such as methanol, ethanol, propanol etc.The reaction may be carried out at a temperature in the range of 0° C.to reflux temperature of the solvent used, preferably at a temperaturein the range of 25° C. to reflux temperature of the solvent used. Theduration of the reaction may range from 0.25 to 48 hrs.

Route 15

[0198] The reaction of a compound of formula (IVg) where all symbols areas defined earlier with a compound of formula (IVc) where R⁹ is asdefined earlier to produce a compound of formula (I) (by a rhodiumcarbenoid mediated insertion reaction) may be carried out in thepresence of rhodium (II) salts such as rhodium (II) acetate. Thereaction may be carried out in the presence of solvents such as benzene,toluene, dioxane, ether, TBF and the like or a combination thereof orwhen practicable in the presence of R⁹OH as solvent at any temperatureproviding a convenient rate of formation of the required product,generally at an elevated temperature, such as reflux temperature of thesolvent. The inert atmosphere may be maintained by using inert gasessuch as N₂, Ar, or He. The duration of the reaction may range from 0.5to 24 h, preferably from 0.5 to 6 h.

[0199] The compound of general formula (I) where Y represents oxygen andR¹⁰ is as defined earlier may be converted to compound of formula (I),where Y represents NR¹² by reaction with appropriate amines of theformula NHR¹⁰R¹², where R¹⁰ and R¹² are as defined earlier. Suitably thecompound of formula (I) where YR¹⁰ represents OH may be converted toacid halide, preferably YR¹⁰=Cl, by reacting with appropriate reagentssuch as oxalyl chloride, thionyl chloride and the like, followed bytreatment with amines. Alternatively, mixed anhydrides may be preparedfrom compound of formula (I) where YR¹⁰ represents OH and all othersymbols are as defined earlier by treating with acid halides such acetylchloride, acetyl bromide, pivaloyl chloride, dichlorobenzoyl chlorideand the like. The reaction may be carried out in the presence ofsuitable base such as pyridine, triethylamine, diisopropyl ethyl amineand the like. Solvents such as halogenated hydrocarbons like CHCl₃, orCH₂Cl₂; hydrocarbons such as benzene, toluene, xylene and the like maybe used. The reaction may be carried out at a temperature in the rangeof 40° C. to 40° C., preferably at a temperature in the range of 0° C.to 20° C. The acid halide or mixed anhydride thus prepared may furtherbe treated with appropriate amines.

[0200] In another embodiment of the present invention the novelintermediate of formula (IVf)

[0201] where the groups R¹, R², R³, R⁴, and the groups R⁵ and R⁶ whenattached to a carbon atom, may be same or different and representhydrogen, halogen, hydroxy, nitro, cyano, formyl or optionallysubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;R⁵ and R⁶ when attached to nitrogen atom represents hydrogen, hydroxy,formyl or optionally substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl,heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino,alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy,heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio,thioalkyl groups, carboxylic acid derivatives, or sulfonic acidderivatives; one or both of R⁵ and R⁶ may also represent an oxo groupwhen they are attached to carbon atom; X represents a heteroatomselected from oxygen, sulfur or NR¹¹ where R¹¹ is selected from hydrogenor optionally substituted groups selected from alkyl, cycloalkyl, aryl,aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonylgroups; Ar represents an optionally substituted divalent single or fusedaromatic or heterocyclic group; R⁷ represents hydrogen atom, hydroxy,alkoxy, halogen, lower alkyl, or optionally substituted aralkyl group;R⁸ represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group,acyl, optionally substituted aralkyl group; R⁹ represents hydrogen, oroptionally substituted groups selected from alkyl, cycloalkyl, aryl,aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,or heteroaralkyl groups; the linking group represented by(CH₂)_(n)-(O)_(m)- may be attached either through nitrogen atom orcarbon atom; n is an integer ranging from 1-4 and m is an integer 0 or 1and a process for its preparation and its use in the preparation ofβ-aryl-α-substituted hydroxyalkanoic acids is provided.

[0202] The compound of formula (IVf) where R⁷ and R⁸ each representhydrogen atoms and all other symbols are as defined earlier is preparedby a process outlined in Scheme-III.

[0203] The reaction of a compound of formula (IIIa) where all symbolsare as defined earlier with a compound of formula (IVh) where R⁹ is asdefined earlier and Hal represents a halogen atom such as Cl, Br, or Imay be carried out under conventional conditions in the presence of abase. The base is not critical. Any base normally employed for Wittigreaction may be employed, metal hydride such as NaH, or KH; metalalkoxides such as NaOMe, K^(t)BuO⁻, or NaOEt; or metal amides such asLiNH₂, or LiN(ipr)₂. Aprotic solvent such as THF, DMSO, dioxane, DME andthe like may be used. Mixture of solvents may be used. HMPA may be usedas a cosolvent. Inert atmosphere may be employed such as argon and thereaction is more effective under anhydrous conditions. Temperature inthe range of −80° C. to 100° C. may be used.

[0204] The compound of (IVi) where all symbols are as defined earliermay be converted to a compound of formula (IVj) where R⁷ and R⁸represent hydrogen atoms and all other symbols are as defined earlier,by treating with an alcohol under anhydrous conditions in the presenceof a strong anhydrous acid such as p-toluenesulfonic acid.

[0205] The compound of formula (IVj) defined above upon treatment withtrialkylsilyl cyanide such as trimethylsilyl cyanide produces a compoundof formula (IVf) where R⁷ and R⁸ represent hydrogen atoms and all othersymbols are as defined earlier.

[0206] In still another embodiment of the present invention the novelintermediate of formula (IVg)

[0207] where the groups R¹, R², R³, R⁴, and the groups R⁵ and R⁶ whenattached to a carbon atom, may be same or different and representhydrogen, halogen, hydroxy, nitro, cyano, formyl or optionallysubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy,aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl,heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;one or both of R⁵ and R⁶ may also represent an oxo group when they areattached to a carbon atom; R⁵ and R⁶ when attached to a nitrogen atomrepresents hydrogen, hydroxy, formyl or optionally substituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl,heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl,amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl,aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,or sulfonic acid derivatives; X represents a heteroatom selected fromoxygen, sulfur or NR¹¹ where R¹¹ is selected from hydrogen or optionallysubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Arrepresents an optionally substituted divalent single or fused aromaticor heterocyclic group; R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, or optionally substituted aralkyl group; R¹⁰represents hydrogen or optionally substituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, orheteroaralkyl groups; Y represents oxygen; the linking group representedby -(CH₂)_(n)-(O)_(m)- may be attached either through nitrogen atom orcarbon atom; n is an integer ranging from 1-4 and m is an integer 0 or 1and a process for its preparation and its use in the preparation ofβ-aryl-α-substituted hydroxyalkanoic acids is provided.

[0208] The compound of formula (IVg) where all other symbols are asdefined earlier may be prepared by reacting a compound of formula (IVk)

[0209] where R⁸ is a hydrogen atom and all other symbols are as definedearlier, with an appropriate diazotizing agent.

[0210] The diazotization reaction may be under conventional conditions.A suitable diazotizing agent is an alkyl nitrile, such as iso-amylnitrile. The reaction may be carried out in presence of solvents such asTHF, dioxane, ether, benzene and the like or a combination thereof.Temperature in the range of −50° C. to 80 may be used. The reaction maybe carried out in an inert atmosphere which may be maintained by usinginert gases such as N₂, Ar or He. The duration of the reaction may rangefrom 1 to 24 h, preferably, 1 to 12 h.

[0211] The compound of formula (IVk) may also be prepared by a reactionbetween (IIIh) where all symbols are as defined earlier and a compoundof formula (IVl)

[0212] where R⁸ is a hydrogen atom and all other symbols are as definedearlier.

[0213] The reaction of compound of formula (IIIh) where all symbols areas defined earlier and a compound of formula (IVl) where all symbols areas defined earlier may be carried out in the presence of solvents suchas THF, DMF, DMSO, DME and the like or mixtures thereof. The reactionmay be carried out in an inert atmosphere which is maintained by usinginert gases such as N₂, Ar or He. The reaction may be effected in thepresence of a base such as K₂CO₃, Na₂CO₃ or NaH or mixtures thereof.Acetone may be used as a solvent when K₂CO₃ or Na₂CO₃ is used as a base.The reaction temperature may range from 20° C.-120° C., preferably at atemperature in the range of 30° C.-80° C. The duration of the reactionmay range from 1 to 24 hours, preferably from 2 to 12 hours.

[0214] As used in this application the term neat means the reaction iscarried out without the use of solvent. The pharmaceutically acceptablesalts are prepared by reacting the compound of formula (I) with 1 to 4equivalents of a base such as sodium hydroxide, sodium methoxide, sodiumhydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxideand the like, in solvents like ether, TEF, methanol, t-butanol, dioxane,isopropanol, ethanol etc. Mixtures of solvents may be used. Organicbases like lysine, arginine, diethanolamine, choline, guanidine andtheir derivatives etc. may also be used. Alternatively, acid additionsalts wherever applicable are prepared by treatment with acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, aceticacid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid,ascorbic acid, palmitic acid, succinic acid, benzoic acid,benzenesulfonic acid, tartaric acid and the like in solvents like ethylacetate, ether, alcohols, acetone, THF, dioxane etc. Mixtures ofsolvents may also be used.

[0215] The stereoisomers of the compounds forming part of this inventionmay be prepared by using reactants in their single enantiomeric form inthe process wherever possible or by conducting the reaction in thepresence of reagents or catalysts in their single enantiomer form or byresolving the mixture of stereoisomers by conventional methods. Some ofthe preferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are compiled by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981). More specifically the compound of formula (I) where YR¹⁰represents OH may be converted to a 1:1 mixture of diastereomeric amidesby treating with chiral amines, aminoacids, aminoalcohols derived fromaminoacids; conventional reaction conditions may be employed to convertacid into an amide; the diastereomers may be separated either byfractional crystallization or chromatography and the stereoisomers ofcompound of formula (I) may be prepared by hydrolyzing the purediastereomeric amide.

[0216] Various polymorphs of a compound of general formula (I) formingpart of this invention may be prepared by crystallization of compound offormula (I) under different conditions. For example, using differentsolvents commonly used or their mixtures for recrystallization;crystallizations at different temperatures; various modes of cooling,ranging from very fast to very slow cooling during crystallizations.Polymorphs may also be obtained by heating or melting the compoundfollowed by gradual or fast cooling. The presence of polymorphs may bedetermined by solid probe nmr spectroscopy, ir spectroscopy,differential scanning calorimetry, powder X-ray diffraction or suchother techniques.

[0217] The present invention also provides pharmaceutical compositions,containing a compounds of the general formula (I), as defined above,their tautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts, their pharmaceutically acceptablesolvates in combination with the usual pharmaceutically employedcarriers, diluents and the like, useful in reducing body weight and forthe treatment and/or prophylaxis of diseases such as hypertension,coronary heart disease, atherosclerosis, stroke, peripheral vasculardiseases and related disorders. These compounds are useful for thetreatment of familial hypercholesterolemia, hypertriglyceridemia,lowering of atherogenic lipoproteins, VLDL and LDL. The compounds of thepresent invention can be used for the treatment of certain renaldiseases including glomerulonephritis, glomerulosclerosis, nephroticsyndrome and hypertensive nephrosclerosis. The compounds of generalformula (I) are also useful for the treatment/prophylaxis of insulinresistance (type II diabetes), impaired glucose tolerance, dyslipidemia,disorders related to syndrome X such as hypertension, obesity, insulinresistance, coronary heart disease, and other cardiovascular disorders.These compounds may also be useful as aldose reductase inhibitors, forimproving cognitive functions in dementia, treating diabeticcomplications, disorders related to endothelial cell activation,psoriasis, polycystic ovarian syndrome (PCOS) and osteoporosis.

[0218] The pharmaceutical composition may be in the forms normallyemployed, such as tablets, capsules, powders, syrups, solutions,suspensions and the like, may contain flavorants, sweeteners etc. insuitable solid or liquid carriers or diluents, or in suitable sterilemedia to form injectable solutions or suspensions. Such compositionstypically contain from 1 to 20%, preferably 1 to 10% by weight of activecompound, the remainder of the composition being pharmaceuticallyacceptable carriers, diluents or solvents.

[0219] The compound of the formula (I) as defined above are clinicallyadministered to mammals, including man, via either oral or parenteralroutes. Administration by the oral route is preferred, being moreconvenient and avoiding the possible pain and irritation of injection.However, in circumstances where the patient cannot swallow themedication, or absorption following oral administration is impaired, asby disease or other abnormality, it is essential that the drug beadministered parenterally. By either route, the dosage is in the rangeof about 0.01 to about 50 mg/kg body weight of the subject per day orpreferably about 0.01 to about 30 mg/kg body weight per day administeredsingly or as a divided dose. However, the optimum dosage for theindividual subject being treated will be determined by the personresponsible for treatment, generally smaller doses being administeredinitially and thereafter increments made to determine the most suitabledosage.

[0220] Suitable pharmaceutically acceptable carriers include solidfillers or diluents and sterile aqueous or organic solutions. The activecompound will be present in such pharmaceutical compositions in theamounts sufficient to provide the desired dosage in the range asdescribed above. Thus, for oral administration, the compounds can becombined with a suitable solid, liquid carrier or diluent to formcapsules, tablets, powders, syrups, solutions, suspensions and the like.The pharmaceutical compositions, may, if desired, contain additionalcomponents such as flavorants, sweeteners, excipients and the like. Forparenteral administration, the compounds can be combined with sterileaqueous or organic media to form injectable solutions or suspensions.For example, solutions in sesame or peanut oil, aqueous propylene glycoland the like can be used, as well as aqueous solutions of water-solublepharmaceutically-acceptable acid addition salts or salts with base ofthe compounds. The injectable solutions prepared in this manner can thenbe administered intravenously, intraperitoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans.

[0221] The invention is explained in detail in the examples given belowwhich are provided by way of illustration only and therefore should notbe construed to limit the scope of the invention.

Preparation 1

[0222] 4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde:

[0223] A mixture of 2H-1,4-benzoxazin-3-(4H)-one (1.6 g, 10.7 mmol),4-(2-bromoethoxy)benzaldehyde (2.95 g, 12.8 mmol) and potassiumcarbonate (5.93 g, 42.97 mmol) in dry dimethyl formamide (30 mL) wasstirred at 80° C. for 10 h.. Water (100 mL) was added and extracted withethyl acetate (2×75 mL). The combined organic layers were washed withwater (50 mL), brine (50 mL), dried (Na₂SO₄), filtered and the solventwas evaporated. The residue was chromatographed over silica gel using amixture of ethyl acetate and pet. ether (2: 8) to afford the titlecompound (2.9 g, 91%) as a colorless solid. mp : 75-78° C.

[0224]¹H NMR (CDCl₃, 200 MHz) : δ 4.37 (s, 4H), 4.62 (s, 2H), 6.96-7.26(complex, 6H), 7.82 (d, J=8.4 Hz, 2H), 9.89 (s, 1H).

Preparation 2

[0225] 6[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]cyanonaphthalene:

[0226] A mixture of 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethylmethanesulfonate (0.49 g, 1.82 mmol), 2-hydroxy-6-cyanonaphthalene(0.28, 1.65 mmol) and potassium carbonate (1.15 g, 8.28 mmol) in drydimethyl formamide (15 mL) was stirred at 80° C. for 12 h. Water (50 mL)was added and extracted with ethyl acetate (2×25 mL). The combined ethylacetate layer was washed with water (25 mL), brine (20 mL), dried(Na₂SO₄), filtered and the solvent was evaporated under reducedpressure. The residue was chromatographed over silica gel using amixture of ethyl acetate and pet. ether to afford the title compound(0.41 g, 72%) as a pale yellow solid. mp : 94-96° C.

[0227]¹H NMR (CDCl₃, 200 MHz): δ 3.05 (t, J=5.21 Hz, 2H), 3.79-3.85(complex, 4H), 4.31 (t, J=5.82 Hz, 2H), 6.64-6.78 (complex, 2H),6.97-7.25 (complex, 4H), 7.53-7.80 (complex, 3H), 8.13 (s, 1H).

Preparation 3

[0228] 6[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxylnaphthaldehyde:

[0229] To a solution of6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]cyanonaphthalene (8 g,22.9 mmol) obtained in preparation 2 in dry tetrahydrofuran (15 mL) wasadded diisobutyl aluminum hydride (93 mL, 20% in toluene) at −70° C.over a period of 1 h. After the addition reaction mixture was stirred at25° C. for 16 h. At the end of this time, ethyl formate (20 mL) wasadded and stirred for 1 h at 25° C. Saturated ammonium chloride solution(15 mL) was added. The reaction mixture was acidified with 10% sulphuricacid and extracted with ethyl acetate (2×75 mL). The combined ethylacetate layer was washed with water (2×50 mL), brine (50 mL), dried(Na₂SO₄), filtered and the solvent was evaporated under reducedpressure. The residue was chromatographed over silica gel using amixture of ethyl acetate and pet. ether (10:90) to afford the titlecompound (4.5 g, 56%) as a pale yellow solid. mp: 100-102° C.

[0230]¹H NMR (CDCl₃, 200 MHz): δ 3.06 (t, J=5.2 Hz, 2H), 3.72-3.86(complex, 4H), 4.33 (t, J=5.67 Hz, 2H), 6.60-6.79 (complex, 2H),6.97-7.25 (complex, 4H), 7.74-7.93 (complex, 3H), 8.25 (s, 1H), 10.09(s, 1H).

Preparation 4

[0231]4-[4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methoxybenzaldehyde:

[0232] To a solution of4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-methanol (6.0 g, 33.51 mmol) indichloromethane (20 mL) was added triethylamine (10.15 g, 100.5 mmol)under nitrogen atmosphere at 25° C. Methanesulfonyl chloride (5.75 g,50.25 mmol) was added to the above reaction mixture at 0° C. andstirring was continued for further 10 h at 25° C. Water (50 mL) wasadded and extracted with chloroform (2×25 mL). The combined organicextracts were washed with water (50 mL), dried (Na₂SO₄), filtered andthe solvent was evaporated under reduced pressure. The residue waschromatographed over silica gel using a mixture of ethyl acetate andhexane (2:8) to yield(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl methanesulfonate(3.7 g, 43%) as a syrup.

[0233]¹H NMR (CDCl₃, 200 MHz): δ 2.88 (s, 3H), 3.07 (s, 3H), 3.13-3.31(complex, 2H), 4.41 (d, J=5.2 Hz, 2H), 4.53-4.55 (complex, 1H),6.81-6.89 (complex, 4H). A mixture of(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-4-yl)methyl methanesulfonate(3.7 g, 14.39 mmol), 4-hydroxy benzaldehyde (2.6 g, 21.29 mmol) andpotassium carbonate (5.9 g, 42.7 mmol) in dry dimethyl formamide (30 mL)was stirred at 80° C. for 10 h. Water (100 mL) was added and extractedwith ethyl acetate (2×70 mL). The combined organic layers were washedwith water (50 mL), brine (50 mL) and dried (Na₂SO₄), filtered and thesolvent was evaporated under reduced pressure. The residue waschromatographed over silica gel using a mixture of ethyl acetate andpet. ether (2:8) to afford the title compound (1.3 g, 32%) as a thickliquid.

[0234]¹H NMR (CDCl₃, 200 MHz): δ 2.93 (s, 3H), 3.24-3.46 (complex, 2H),4.14-4.37 (complex, 2H), 4.68-4.71 (complex, 1H), 6.72-7.10 (complex,6H), 7.86 (d, J=8.8 Hz, 2H), 9.92 (s, 1H).

Preparation 5

[0235]4-[4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methoxybenzaldehyde:

[0236] The title compound (3.2 g, 80%) was prepared as a pale yellowsolid from 4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-methanol (4.0 g,15.68 mmol) by a procedure similar to that described for preparation 4.mp : 92-94° C.

[0237]¹H NMR (CDCl₃, 200 MHz) : δ 3.38-3.43 (complex, 2H), 4.14-4.32(complex, 2H), 4.46 (d, J=7.8 Hz, 2H), 4.60-4.65 (complex, 1H),6.65-6.89 (complex, 4H), 7.00 (d, J=8.8 Hz, 2H), 7.32 (s, 5H), 7.83 (d,J=8.8 Hz, 2H), 9.90 (s, 1H).

EXAMPLE 1

[0238] Ethyl(E/Z)-3-[4-[2-2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate:

[0239] A solution of triethyl 2-ethoxyphosphonoacetate (W. Grell and H.Machleidt, Annalen Chemie, 1960, 699, 53). (7.8 g, 29.1 mmol) in drytetrahydrofuran (15 mL) was added slowly to a stirred, ice-cooledsuspension of sodium hydride (60% dispersion in oil) (1.39 g, 29.1 mmol)in dry tetrahydrofuran (5 mL) under nitrogen atmosphere. The mixture wasstirred at 0° C. for 30 minutes followed by the addition of a solutionof 4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde (7.5 g,26.5 mmol) which is prepared according to the process described inPreparation 1 disclosed in U.S. patent application Ser. No. 08/982,910,in dry tetrahydrofuran (20 mL). The mixture was allowed to warm to 25°C. and stirred further for 20 h. The solvent was evaporated and theresidue was suspended in water (100 mL) and extracted with ethyl acetate(2×75 mL). The combined ethyl acetate layers were washed with water (75mL), brine (50 mL), dried (Na₂SO₄), filtered and the solvent wasevaporated under reduced pressure. The residue was chroniatographed oversilica gel using a mixture of ethyl acetate and petroleum ether (2:8) aseluent to afford the title compound (8.0 g, 75%) a gum as a 65:35 Z:Emixture of geometric isomers (R. A. Aitken and G. L. Thom, Synthesis,1989, 958).

[0240]¹H NMR (CDCl₃, 200 MHz) δ: 1.18 and 1.36 (combined 6H, isomericOEt, triplet signals), 3.51 (t, J=4.48 Hz, 2H), 3.71 (t, J=5.39 Hz, 2H),3.89-4.03 (complex, 2H), 4.10-4.34 (complex, 6H), 6.07 (s, 0.35H, Eolefinic proton), 6.63-7.14 (complex, 6.65H), 7.73 (d, J=8.72 Hz, 2H).

EXAMPLE 2

[0241] Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate

[0242] A mixture of ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate(8.0 g, 20.0 mmol) obtained in example 1 and magnesium turnings (9.64 g,396.7 mmol) in dry methanol (50 mL) was stirred at 25° C. for 20 h. Atthe end of this time water (50 mL) was added and pH was adjusted to ca7.0 using 10% aqueous hydrochloric acid and the solution was extractedwith ethyl acetate (2×10 mL). The combined organic extract was washedwith water (75 mL), brine (75 mL), dried (Na₂SO₄), filtered and thesolvent was removed under reduced pressure. The residue waschromatographed over silica gel using a mixture of ethyl acetate andpet. ether (2:8) as an eluent to get the title compound (5.0 g, 64%) asa gummy liquid.

[0243]¹H NMR (CDCl₃, 200 MHz) δ: 1.15 (t, J=7.0 Hz, 3H), 2.93 (d, J=6.64Hz, 2H), 3.23-3.38 (complex, 1H), 3.43-3.72 (complex, 8H), 3.97 (t,J=6.9 Hz, 1H), 4.14 (t, J=5.81 Hz, 2H), 4.19 (t, J=4.2 Hz, 2H),6.55-6.83 (complex, 6H), 7.13 (d, J=8.39 Hz, 2H).

EXAMPLE 3

[0244] Ethyl(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate:

[0245] The title compound (0.8 g, 58%) was prepared as a gummy materialfrom 5-formyl-2-(2,3-dihydro-1,4-benzoxazin-4-yl)methyl benzofuran (1.0g, 3.41 mmol) by a procedure analogous to that described in example 1.

[0246]¹H NMR (CDCl₃, 200 MHz) δ: 1.06 and 1.38 ( 6H, OCH₂CH₃ andOCH₂CH₃, triplet signals), 3.48 (t, J=4.98 Hz, 2H), 3.89-4.18 (complex,2H), 4.28-4.40 (complex, 4H), 4.54 and 4.56 (combined, 2H,-NCH₂-signals), 6.20 (0.5 H, E isomer of olefinic proton), 6.52 and 6.59(combined, 1H), 6.65-6.83 (complex, 2.5 H), 7.08-7.11 (complex, 1H),7.32-7.44 (complex, 2H), 7.69 (d, J=8.3 Hz, 1H), 7.99 (s, 1H).

EXAMPLE 4

[0247] Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate:

[0248] The title compound was prepared as a 38:62 ratio of geometricisomers (as measured by ¹H NMR) (3.2 g, 71%) as a gum, from4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]benzaldehyde (3.3 g,11.03 mmol) prepared according to the process described in Preparation 2disclosed in Patent Application 08/982,910 by a method analogous to thatdescribed in example 1.

[0249]¹H NMR (CDCl₃, 200 MHz) δ: 1.14 and 1.35 (combined, 6H, isomeric-OCH₂CH₃ triplet signals), 3.02 (t, J=4.9 Hz, 2H), 3.69-3.88 (complex,4H), 3.92-4.03 (complex, 2H), 4.12-4.33 (complex, 4H), 6.06 (s, 0.38 H,E olefinic proton), 6.61-7.14 (complex, 6.62 H), 7.73 (d, J=8.81 Hz,2H).

EXAMPLE 5

[0250] Methyl3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate:

[0251] The title compound (0.6 g, 78%) was prepared as a gum from Ethyl(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate(0.8 g, 1.96 mmol) obtained in example 3 by a procedure analogous tothat described for example 2.

[0252]¹H NMR (CDCl₃, 200 MHz) δ: 1.15 (t, J=7.0 Hz, 3H), 3.07 (d,J=5.8Hz, 2H), 3.28-3.67 (complex, 4H), 3.70 (s, 3H), 4.03 (t, J=6.0 Hz,1H), 4.28 (t, J=4.47 Hz, 2H), 4.54 (s, 2H), 6.52 (s, 1H), 6.62-6.89(complex, 4H), 7.10 (d, J=7.05 Hz, 1H), 7.35 (complex, 2H).

EXAMPLE 6

[0253]Methyl-3-[4-12-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate:

[0254] The title compound (2.3 g, 76%) was prepared as a gummy liquidfrom ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate( 3.1 g, 7.50 mmol) obtained in example 4 by an analogous procedure tothat described in example 2.

[0255]¹H NMR (CDCl₃, 200 MHz) δ: 1.15 (t, J=7.01 Hz, 3H), 2.93 (d,J=6.65 Hz, 2H), 3.03 (t, J=5.21 Hz, 2H), 3.23-3.41 (complex, 1H),3.52-3.80 (complex, 8H), 3.97 (t, J=7.01 Hz, 1H), 4.14 (t, J=5.81 Hz,2H), 6.61-6.82 (complex, 4H), 6.92-7.05 (complex, 2H), 7.13 (d, J=8.53Hz, 2H).

EXAMPLE 7

[0256] Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate:

[0257] To a solution of methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(0.6 g, 1.5 mmol) obtained in example 2 in dry tetrahydrofuran (5 mL)was added lithium diisopropyl amide (5.25 μL, 0.5 mL solution inTHF/hexane) at −78° C. After stirring for 1 h at −78 ° C., methyl iodide(0.75 mL) was added and the reaction mixture was allowed to warm to roomtemperature (ca 25° C.) and stirred for further 20 h at the sametemperature. Water (20 mL) was added, acidified with 1 N hydrochloricacid and extracted with ethyl acetate (2×25 mL). The combined ethylacetate layer was washed with water (25 mL), brine (25 mL), dried(Na₂SO₄), filtered and the solvent was evaporated under reduced pressureto afford the title compound (0.5 g, 80%) as an oil.

[0258]¹H NMR (CDCl₃, 200 MHz): δ 1.21 (t, J=6.97 Hz, 3H), 1.31 (s, 3H),2;95 (s, 2H), 3.32-3.58 (complex, 4H), 3.62-3.84 (complex, 5H), 4.14 (t,J=5.81 Hz, 2H), 4.22 (t, J=4.25 Hz, 2H), 6.55-6.88 (complex, 6H), 7.08(d, J=8.63 Hz, 2H).

EXAMPLE 8

[0259] Methyl2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate:

[0260] The title compound (0.6 g, 78%) was prepared as a brown liquidfrom methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(0.6 g, 1.5 mmol) obtained in example 2 by an analogous procedure tothat described in example 7.

[0261]¹H NMR (CDCl₃, 200 MHz) δ: 1.22 (t, J=6.96 Hz, 3H), 3.03-3.18(complex, 4H), 3.51 (t, J=4.2 Hz, 2H), 3.59-3.71 (complex, 7H), 4.14 (t,J=5.81 Hz, 2H), 4.22 (t, J=4.24 Hz, 2H), 6.42-6.85 (complex, 6H),6.90-7.32 (complex 6H).

EXAMPLE 9

[0262] Ethyl(E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate

[0263] The title compound (3.9 g, 97%) was obtained in 32:68 ratio ofE:Z isomers as a white solid from4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde (2.9 g, 9.7 mmol)obtained in preparation 1 by an analogous procedure to that described inexample 1. mp: 92-95° C.

[0264]¹H NMR (CDCl₃, 200 MHz) δ: 1.13-1.43 (complex, 6H), 3.88-4.02(complex, 2H), 4.07-4.40 (complex, 6H), 4.60 (s, 2H), 6.05 (s, 0.32 H, Eolefinic proton), 6.76-7.32 (complex, 6.68 H), 7.71 (d, J=8.72 Hz, 2H).

EXAMPLE 10

[0265] Methyl3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate:

[0266] The title compound (1.0 g, 51%) was prepared as a colorless syrupfrom ethyl(E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate(2.0 g, 4.8 mmol) obtained in example 9 by a procedure analogous to thatdescribed in example 2.

[0267]¹H NMR (CDCl₃, 200 MHz): δ: 1.14 (t, J=7.0 Hz, 3H), 2.92 (d, J=6.6Hz, 2H), 3.25-3.41 (complex, 1H), 3.53-3.61 (complex, 1H), 3.68 (s, 3H),3.96 (t, J=7.0 Hz, 1H), 4.21-4.32 (complex, 4H), 4.68 (s, 2H), 6.77 (d,J=8.63 Hz, 2H), 6.98-7.33 (complex, 6H).

EXAMPLE 11

[0268] Ethyl(E/Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropenoate:

[0269] The title compound as a 1:1 mixture of E/Z isomers (1.74 g, 87%)was prepared as a brown syrup from6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthaldehyde (1.5 g,4.29 mmol) obtained in preparation 3 by a procedure analogous to thatdescribed in example 1.

[0270]¹H NMR (CDCl₃, 200 MHz): δ 0.99-1.47 (complex, 6H), 3.06 (t,J=4.98 Hz, 2H), 3.79-3.95 (complex, 4H), 3.99-4.18 (complex, 2H),4.25-4.37 (complex, 4H), 6.23 (s, 0.5 H, E olefinic proton), 6.59-6.79(complex, 2H), 6.97-7.29 (complex, 4.5H), 7.57-7.95 (complex, 3H), 8.14(s, 1H).

EXAMPLE 12

[0271] Methyl3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate:

[0272] The title compound (1.25 g, 75%) was prepared as a colorlesssyrup from ethyl(E/Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropenoate(1.7 g, 3.67 mmol) obtained in example 11 by an analogous procedure tothat described in example 2.

[0273]¹H NMR (CDCl₃, 200 MHz) : δ 1.14 (t, J=7.06 Hz, 3H), 3.06 (t,J=5.21 Hz, 2H), 3.13 (d, J=7.15 Hz, 2H), 3.29-3.37 (complex, 1H),3.57-3.64 (complex, 1H), 3.70 (s, 3H), 3.77-3.83 (complex, 4H), 4.09 (t,J=7.2 Hz, 1H), 4.25 (t, J=5.81 Hz, 2H), 6.62-6.79 (complex, 2H),6.96-7.36 (complex, 5H), 7.60-7.70 (complex, 3H).

EXAMPLE 13

[0274] Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate:

[0275] The title compound (0.14 g, 32%) was prepared as a gummy liquidfrom 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethyl methanesulfonate (0.36 g,1.42 mmol), potassium carbonate (0.80 g, 5.8 mmol) and ethyl2-hydroxy-3-(4-hydroxyphenyl)propanoate (0.3 g, 1.42 mmol) usingconditions analogous to that described in preparation 2.

[0276]¹H NMR (CDCl₃, 200 MHz) : δ 1.24 (t, J=7.15 Hz, 3H), 2.71 (d,J=6.23 Hz, 1H, D₂O exchangeable), 2.84-3.10 (complex, 2H), 3.50 (t,J=4.47 Hz, 2H), 3.67 (t, J=5.48 Hz, 2H), 4.11-4.26 (complex, 6H),4.37-4.39 (complex, 1H), 6.61-6.86 (complex, 6H), 7.11 (d, J=8.62 Hz,2H).

EXAMPLE 14

[0277] Ethyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate:

[0278] The title compound (1.9 g, 17%) was prepared as a gummy liquidfrom 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethyl methanesulfonate (8.2 g,30.0 mmol), potassium carbonate (20.7 g, 150 mmol) and ethyl2-hydroxy-3-(4-hydroxyphenyl)propanoate (6.3 g, 30.0 mmol) usingconditions analogous to that described in preparation 2.

[0279]¹H NMR (CDCl₃, 200 MHz) : δ 1.29 (t, J=7.11 Hz, 3H), 2.70-2.80(bs, 1H, D₂O exchangeable), 2.82-3.15 (complex, 4H), 3.65-3.82 (complex,4H), 4.10-4.30 (complex, 4H), 4.28-4.40 (complex, 1H), 6.62-6.89(complex, 4H), 6.92-7.18 (complex, 4H).

EXAMPLE 15

[0280] Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate:

[0281] A solution of ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate(0.5 g, 1.34 mmol) obtained in example 13 in dry dimethyl formamide (5mL) was added to a stirred ice cooled suspension of sodium hydride (60%dispension in oil) (0.08 g, 1.66 mmol) in dry dimethyl formamide (3 mL)under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for30 minutes followed by the addition of benzyl bromide (0.46 g, 2.69mmol). The mixture was allowed to warm to 25° C. and stirring wascontinued for fuirther 18 h. Water (25 mL) was added and extracted withethyl acetate (2×50 mL). The combined organic layer was washed withwater (50 mL), brine (50 mL) and dried Na₂SO₄ and filtered. The solventwas evaporated under reduced pressure and the residue waschromatographed over silica gel using a mixture of ethyl acetate andpet. ether (2:8) as eluent to afford the title compound (0.3 g) alongwith benzyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate.This mixture (1:1) is used in example 47 without any separation.

[0282]¹H NMR (CDCl₃, 200 MHz) : δ 1.23 (t, J=7.05 Hz, 1.5H), 2.99 (d,J=7.06 Hz, 4H), 3.0-3.72 (complex, 8H), 4.05-4.30 (complex, 12H),4.32-4.71 (complex, 4H), 5.13 (s, 2H), 6.55-689 (complex, 12H),7.05-7.36 (complex, 19H).

EXAMPLE 16

[0283] Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate:

[0284] The title compound (0.4 g, 52%) was prepared as a gummy liquidfrom 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethyl methanesulfonate (0.46 g;1.78 mmol), potassium carbonate (0.98 g, 7.12 mmol) and ethyl2-butoxy-3-(4-hydroxyphenyl)propanoate (0.47 g, 1.78 mmol) usingconditions analogous to that described in preparation 2.

[0285]¹H NMR (CDCl₃, 200 MHz): δ 0.84 (t, J=7.53 Hz, 3H), 1.19-1.34(complex, 5H), 1.43-1.55 (complex, 2H), 2.92 (d, J=6.32 Hz, 2H),3.22-3.36 (complex, 1H), 3.48-3.59 (complex, 3H), 3.68 (t, J=5.82 Hz,2H), 3.93 (t, J=6.2 Hz, 1H), 4.11-4.24 (complex, 6H), 6.61-6.86(complex, 6H), 7.13 (d, J=8.3 Hz, 2H).

EXAMPLE 17

[0286] Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoate:

[0287] The title compound (0.31 g, 50%) was prepared as a colorlesssyrup from 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethyl methanesulfonate(0.35 g, 1.3 mmol), potassium carbonate (0.75 g, 5.4 mmol) and ethyl2-hexyloxy-3-(4-hydroxyphenyl) propanoate (0.4 g, 1.3 mmol) usingconditions analogous to that described in preparation 2.

[0288]¹H NMR (CDCl₃, 200 MHz): δ 0.85 (t, J=5.72 Hz, 3H), 1.20-1.34(complex, 7H), 1.40-1.66 (complex, 4H), 2.93 (d, J=6.0 Hz, 2H),3.21-3.31 (complex, 1H), 3.49-3.60 (complex, 3H), 3.68 (t, J=5.72 Hz,2H), 3.93 (t, J=5.81 Hz, 1H), 4.11-4.24 (complex, 6H), 6.62-6.81(complex, 5 H), 7.09-7.16 (complex, 3H).

EXAMPLE 18

[0289] Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate:

[0290] The title compound (0.92 g, 58%) was prepared as a mixture of E:Z isomers (40:60) as a syrupy liquid from4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde (1.0 g, 3.0mmol) and triethyl 2-phenoxyphosphonoacetate (A. G. Schultz, et. al. JOrg. Chem., 1983, 48, 3408) (1.3 g, 4.0 mmol) by an analogous procedureto that described in example 1.

[0291]¹H NMR (CDCl₃, 200 MHz) : δ 1.06 and 1.18 (combined 3H, isomericOCH₂CH₃, triplet singals), 3.43-3.57 (complex, 2H), 3.64-3.75 (complex,2H), 4.06-4.28 (complex, 6H), 6.60-6.90 (complex, 8H), 6.94-7.12(complex, 2H), 7.22-7.45 (complex, 3H), 7.64 (d, J=8.72 Hz, 1H).

EXAMPLE 19

[0292] Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate:

[0293] The title compound (0.49 g, 57%) was prepared as a gummy materialfrom ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate(0.9 g, 2.0 mmol) obtained in example 18 by an analogous procedure tothat described for example 2.

[0294]¹H NMR (CDCl₃, 200 MHz): δ 3.17 (d, J=6.2 Hz, 2H), 3.50 (t, J=4.3Hz, 2H), 3.65-3.70 (complex, 5H), 4.14 (t, J=5.76 Hz, 2H), 4.21 (t,J=4.15 Hz, 2H), 4.75 (t, J=6.4 Hz, 1H), 6.61-6.98 (complex, 9H),7.17-7.27 (complex, 4H).

EXAMPLE 20

[0295] Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate:

[0296] The title compound (3.7 g, 60%) was prepared as a mixture of E: Zisomers (35:65) as a gummy material from4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]benzaldehyde (4.0 g, 13.0mmol) and triethyl 2-phenoxyphosphonoacetate (A. G. Schultz, et. al. J.Org. Chem. 1983, 48, 3408), (5.07 g, 16.0 mmol) by an analogousprocedure to that described in example 1.

[0297]¹H NMR (CDCl₃, 200 MHz): δ 1.05-1.36 (complex, 3H), 3.00-3.11(complex, 2H), 3.64-3.85 (complex, 4H), 4.09-4.30 (complex, 4H),6.58-7.13 (complex, 8H), 7.20-7.46 (complex, 4H), 7.65 (d, J=8.7 Hz,2H).

EXAMPLE 21

[0298] Methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate:

[0299] The title compound (2.3 g, 64%) was prepared as a gummy materialfrom ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate(3.7 g, 8.0 mmol) obtained in example 20 by an analogous procedure tothat described for example 2.

[0300]¹H NMR (CDCl₃, 200 MHz) : δ 2.99 (t, J=5.439 Hz, 2H), 3.15 (d,J=5.99 Hz, 2H), 3.60-3.78 (complex, 7H), 4.13 (t, J=5.4 Hz, 2H), 4.74(t, J=6.23 Hz, 1H), 6.58-6.89 (complex, 6H), 6.90-7.06 (complex, 2H),7.11-7.30 (complex, 5H).

EXAMPLE 22

[0301] Ethyl(E/Z)-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate:

[0302] The title compound (0.4 g, 25%) was prepared as a mixture of E: Zisomers (1:1) as a brown liquid from4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxybenzaldehyde (1.2g, 4.24 mmol) obtained in preparation 4 by an analogous procedure tothat described in example 1.

[0303]¹H NMR (CDCl₃, 200 MHz) : δ 1.36 (t, J=7.1 Hz, 6H), 2.90 (s, 3H),3.26-3.45 (complex, 2H), 3.99 (q, J=7.2 Hz, 2H), 4.10-4.38 (complex,4H), 4.50-4.60 (complex, 1H), 6.70 (d, J=7.47 Hz, 2H), 6.81-6.90(complex, 5H), 7.75(d, J=8.8 Hz, 2H).

EXAMPLE 23

[0304] Methyl3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate:

[0305] The title compound (0.25 g, 65%) was prepared as a thick liquidfrom ethyl(E/Z)-3-[4-(4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate(0.4 g, 1.0 mmol) obtained in example 22 by an analogous procedure tothat described in example 2.

[0306]¹H NMR (CDCl₃, 200 MHz): δ 1.16 (t, J=7.0 Hz, 3H), 2.89 (s, 3H),2.95 (d, J=6.2 Hz, 2H), 3.19-3.41 (complex, 3H), 3.55-3.66 (complex,1H), 3.70 (s, 3H), 3.95-4.24 (complex, 3H), 4.60-4.64 (complex, 1H),6.64-7.08 (complex, 6H), 7.15 (d, J=8.4 Hz, 2H).

EXAMPLE 24

[0307] Ethyl(E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate:

[0308] The title compound (3.0 g, 76%) was prepared as E:Z isomers(1:1), as a syrupy liquid from4-[4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxybenzaldehyde (3.0g, 8.35 mmol) obtained in preparation 5 by a procedure analogous to thatdescribed for example 1.

[0309]¹H NMR (CDCl₃, 200 MHz): δ 1.33 -1.40 (complex, 6H), 3.39-3.44(complex, 2H), 3.99 (q, J=7.0 Hz, 2H), 4.11-4.38 (complex, 4H), 4.46 (d,J=5.0 Hz, 2H), 4.52-4.66 (complex, 1H), 6.60-6.97 (complex, 7H), 7.28(s, 5H), 7.75 (d, J=8.8 Hz, 2H).

EXAMPLE 25

[0310] Methyl3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate:

[0311] The title compound (1.5 g, 100%) was prepared from ethyl(E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate(1.5 g, 3.17 mmol) obtained in example 24 by an analogous procedure tothat described in example 2.

[0312]¹H NMR (CDCl₃, 200 MHz): δ 1.17 (t, J=7.0Hz, 3H), 2.96 (d, J=6.6Hz, 2H), 3.31-3.57 (complex, 3H), 3.60-3.70 (complex, 1H), 3.71 (s, 3H),3.97-4.26 (complex, 3H), 4.47 (d, J=4.0 Hz, 2H), 4.56-4.61 (complex,1H), 6.68-6.90 (complex, 6H), 7.15 (d, J=8.5 Hz, 2H), 7.29 (s, 5H).

EXAMPLE 26

[0313]3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid:

[0314] To a solution of methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate (4.7 g, 12.2 mmol) obtained in example 2 in methanol (50 mL)was added aqueous 10% sodium hydroxide (28 mL). The mixture was stirredat 25° C. for 3h. The solvent was removed under reduced pressure and theresidue was acidified with 2N hydrochloric acid extracted with ethylacetate (×100 mL). The combined ethyl acetate layers were washed withwater (75 mL), brine (50 mL), dried (Na₂SO₄), filtered and the solventwas evaporated under reduced pressure. The residue was chromatographedover silica gel using ethyl acetate to give the title compound (3.0 g,66%) as a syrupy liquid.

[0315]¹H NMR (CDCl₃, 200 MHz) : δ 1.17 (t, J=6.96 Hz, 3H), 2.85-3.12(complex, 2H), 3.40-3.61 (complex, 4H), 3.69 (t, J=5.72 Hz, 2H), 4.04(dd, J=7.38 and 4.27 Hz, 1H), 4.10-4.28 (complex, 4H), 6.52-6.85(complex, 6H), 7.14 (d, J=8.6 Hz, 2H), COOH proton is too broad toobserve.

EXAMPLE 27

[0316]3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, sodium salt:

[0317] A mixture of3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.15 g, 0.4 mmol) obtained in example 26 and sodium methoxide(23.4 mg) in methanol (5 mL) was stirred at 25° C. for 2h. The solventwas removed and the residue was triturated with dry ether (3×10 mL). Theprecipitated solids were filtered, washed with dry ether (2×5 mL) anddried over P₂O₅ under vacuum to afford the title compound (0.12 g, 75%)as a colorless hygroscopic solid.

[0318]¹H NMR (DMSO-d6, 200 MHz): δ 0.98 (t, J=6.83 Hz, 3H), 2.60-2.69(complex, 1H), 2.78-2.92 (complex, 1H), 3.05-3.21 (complex, 2H),3.41-3.75 (complex, 5H), 4.08-4.21 (complex, 4H), 6.49-6.85 (complex,6H), 7.12 (d, J=8.3 Hz, 2H).

EXAMPLE 28

[0319]3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid:

[0320] The title compound (0.5 g, 87%) was prepared as a gummy materialfrom methyl 3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate (0.6 g, 1.51 mmol) obtained inexample 5 by a procedure analogous to that described for example 26.

[0321]¹H NMR (CDCl₃, 200 MHz) δ: 1.26 (t, J=7.06 Hz, 3H), 3.05-3.28(complex, 2H), 3.40-3.68 (complex, 4H), 4.09 (dd, J=7.47 and 4.24 Hz,1H), 4.28 (t, J=4.15 Hz, 2H), 4.53 (s, 2H), 6.52 (s, 1H), 6.60-6.90(complex, 4H), 7.13 (d, J=8.7 Hz, 1H), 7.32-7.36 (complex, 2H), COOHproton is too broad to observe.

EXAMPLE 29

[0322]3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid:

[0323] The title compound (1.4 g, 63%) was prepared as a gummy materialfrom methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(2.3 g, 5.73 mmol) obtained in example 6 by a procedure analogous tothat described for example 26.

[0324]¹H NMR (CDCl₃, 200 MHz) δ: 1.18 (t, J=7.0 Hz, 3H), 2.82-3.15(complex, 4H), 3.40-3.68 (complex, 2H), 3.70-3.81 (complex, 4H), 4.05(dd, J=7.29, 4.33 Hz, 1H), 4.16 (t, J=5.72 Hz, 2H), 6.68-6.74 (complex,2H), 6.81 (d, J=8.5 Hz, 2H), 6.94-7.06 (complex, 2H), 7.14 (d, J=8.5 Hz,2H). COOH proton is too broad to observe.

EXAMPLE 30

[0325]3-[4[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, sodium salt:

[0326] The title compound (0.42 g, 81%) was prepared as a colorlesssolid from3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.5 g, 1.30 mmol) obtained in example 29 by an analogous procedureto that described for example 27.

[0327]¹H NMR (CDCl₃, 200 MHz) : δ 0.98 (t, J=7.0 Hz, 3H), 2.72-3.25(complex, 5H), 3.30-3.51 (complex, 1H), 3.61-3.73 (complex, 4H),3.82-3.91 (complex, 1H), 4.04 (t, J=5.72 Hz, 2H), 6.52-6.79 (complex,4H), 6.91-7.03 (complex, 2H), 7.10 (d, J=8.4 Hz, 2H).

EXAMPLE 31

[0328]3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide:

[0329] A solution of oxalyl chloride (0.28 mL, 3.1 mmol) and3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.6 g, 1.55 mmol) obtained in example 29 in dry dichloromethane(10 mL) was refluxed for 2 h. The solvent and excess oxalyl chloridewere removed under reduced pressure. The residue was dissolved indichloromethane and stirred with aqueous ammonia (5 mL) for 30 min. Thereaction mixture was extracted with chloroform (2×25 mL). The combinedchloroform layer was washed with water (25 mL), dried (Na₂SO₄),filtered, and the solvent was evaporated under reduced pressure. Theresidue was chromatographed over silica gel using a mixture of ethylacetate and pet. ether (7:3) as an eluent to afford the title compound(0.32 g, 54%) as a white solid. mp: 120-122° C.

[0330]¹H NMR (CDCl₃, 200 MHz): δ 1.15 (t, J=6.96 Hz, 3H), 2.81-3.20(complex, 4H), 3.38-3.58 (complex, 2H), 3.71-3.90 (complex, 4H), 3.91(dd, J=7.38 and 3.73 Hz, 1H), 4.16 (t, J=5.58 Hz, 2H), 5.54 (bs, D₂Oexchangeable, 1H), 6.44 (bs, D₂O exchangeable, 1H), 6.59-6.84 (complex,4H), 6.92-7.19 (complex, 4H).

EXAMPLE 32

[0331]N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide:

[0332] To an ice cooled solution of3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.3 g, 0.78 mmol) obtained in example 29 and triethylamine (0.162g, 1.6 mmol) in dry chloromethane (10 mL) was added pivaloyl chloride(0.10 g, 0.86 mmol) and stirring was continued for 30 min at 0° C. Tothe above reaction mixture, methyl amine (40% solution) (0.124 mL) wasadded at 25° C. and stirring was continued for 1 h at 25° C. Water (20mL) was added and extracted with ethyl acetate (2×20 mL). The combinedorganic extract was washed with water (10 mL), brine (10 mL), dried(Na₂SO₄), filtered and the solvent was evaporated under reducedpressure. The residue was chromatographed over silica gel using amixture of ethyl acetate and pet. ether (1:1) to afford the titlecompound as a colorless solid. mp: 80-82° C.

[0333]¹H NMR (CDCl₃, 200 MHz): δ 1.11 (t, J=7.0 Hz, 3H), 2.76 (d, J=4.89Hz, 3H), 2.81-2.88 (complex, 1H), 3.01-3.12 (complex, 3H), 3.39-3.52(complex, 2H), 3.70-3.81 (complex, 4H), 3.86-3.91 (complex, 1H), 4.14(t, J=5.81 Hz, 2H), 6.48 (bs, 1H), 6.61-6.81 (complex, 4H), 6.94-7.14(complex, 4H).

EXAMPLE 33

[0334]3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide:

[0335] The title compound (0.2 g, 80%) was prepared as a white solidfrom3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.25 g, 0.67 mmol) obtained in example 26 and aqueous ammonia (4mL) by an analogous procedure to that described in example 31. mp:107-109° C.

[0336]¹H NMR (CDCl₃, 200 MHz): δ 1.13 (t, J=6.96 Hz 3H), 2.81-2.93(complex, 1H), 3.03-3.19 (complex, 1H), 3.34-3.59 (complex, 4H), 3.69(t, J=5.53 Hz, 2H), 3.88 (dd, J=7.43 and 3.7 Hz, 1H), 4.15 (t, J=5.58Hz, 2H), 4.28 (t, J=4.24 Hz, 2H), 5.49 (bs, 1H, D₂O exchangeable), 6.43(bs, 1H, D₂O exchangeable), 6.68-6.87 (complex, 6H), 7.15 (d, J=8.49 Hz,2H).

EXAMPLE 34

[0337]N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide:

[0338] The title compound (0.23 g, 74%) was prepared as a white solidfrom3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.3 g, 0.8 mmol) obtained in example 26 and methylamine (40%solution) (2 mL) by an analogous procedure to that described in example32. mp: 97-99° C.

[0339]¹H NMR (CDCl₃, 200 MHz): δ 1.14 (t, J=7.0 Hz, 3H), 2.76 (d, J=4.98Hz, 3H), 4.80-4.90 (complex, 1H), 3.02-3.14 (complex, 1H), 3.35-3.45(complex, 2H), 3.52 (t, J=4.57 Hz, 2H), 3.68 (t, J=5.81 Hz, 2H), 7.88(dd, J=7.06 and 3.74 Hz, 1H), 4.14 (t, J=5.72 Hz, 2H), 4.22 (t, J=4.15Hz, 2H), 6.50 (bs, 1H), 6.55-6.89 (complex, 6H), 7.11 (d, J=8.3 Hz, 2H).

EXAMPLE 35

[0340]N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide:

[0341] The title compound (0.25 g, 67%) was prepared as a white solidfrom3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.3 g, 0.8 mmol) obtained in example 26 and benzyl amine (0.095 g,0.88 mmol) by a procedure analogous to that described in example 32. mp:94-96° C.

[0342]¹H NMR (CDCl₃, 200 MHz): δ 1.11 (t, J=7.0 Hz, 3H), 2.82-3.18(complex, 2H), 3.40-3.55 (complex, 4H), 3.70 (t, J=5.49 Hz, 2H),3.94-3.98 (complex, 1H), 4.14 (t, J=5.72 Hz, 2H), 4.23 (t, J=4.24 Hz,2H), 4.28-4.52 (complex, 2H), 6.60-6.87 (complex, 6H), 7.06-7.32(complex, 7H). CONH proton is too broad to observe.

EXAMPLE 36

[0343]N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide:

[0344] The title compound (0.22 g, 74%) was prepared as a white solidfrom3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.25 g, 0.65 mmol) obtained in example 29 and benzylamine (0.076g, 0.71 mmol) by an analogous procedure to that described in example 32.mp : 92-93° C.

[0345]¹H NMR (CDCl₃, 200 MHz): δ 1.15 (t, J=7.0 Hz, 3H), 2.88-3.20(complex, 4H), 3.42-3.60 (complex, 2H), 3.73-3.87 (complex, 4H),3.98-4.06 (complex, 1H), 4.18 (t, J=5.72 Hz, 2H), 4.30-4.56 (complex,2H), 6.61-6.90 (complex, 4H), 7.00-7.43 (complex, 9H), CONH proton istoo broad to observe.

EXAMPLE 37

[0346]2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid:

[0347] The title compound (0.3 g, 62%) was prepared as a gummy liquidfrom methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(0.5 g, 1.2 mmol) obtained in example 7 by an analogous procedure tothat described in example 26.

[0348]¹H NMR (CDCl₃, 200 MHz) δ: 1.24 (complex, 6H), 2.98, 3.04 (1Heach, 2d, J=14.1 Hz each), 3.51 (t, J=4.25 Hz, 2H), 3.49-3.71 (complex,4H), 4.15 (t, J=5.63 Hz, 2H), 4.22 (t, J=4.48 Hz, 2H), 6.60-6.87(complex, 6H), 7.07 (d, J=8.67 Hz, 2H), COOH proton is too broad toobserve.

EXAMPLE 38

[0349]2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, sodium salt:

[0350] The title compound (0.12 g, 51%) was prepared as a white solidfrom2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.22 g, 0.57 mmol) obtained in example 37 by an analogousprocedure to that described in example 27.

[0351]¹H NMR (DMSO-d6, 200 MHz) δ: 0.96-1.08 (complex, 6H), 2.79 (s,2H), 3.28-3.52 (complex, 4H), 3.64 (t, J=5.3 Hz, 2H), 4.05-4.19(complex, 4H), 6.48- 6.59 (complex, 1H), 6.62-6.86 (complex, 4H),7.03-7.28 (complex, 3H).

Example 39

[0352] 2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid:

[0353] The title compound (0.25 g, 42%) was prepared as a gummy liquidfrom methyl2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(0.6 g, 1.2 mmol) obtained in example 8 by an analogous procedure tothat described in example 26.

[0354]¹H NMR (CDCl₃, 200 MHz): δ 1.12 (t, J=6.82 Hz, 3H), 1.65 (bs, 1H,D₂O exchangeable), 3.11-3.42 (complex, 4H), 3.50 (t, J=4.34 Hz, 2H),3.68 (t, J=5.67 Hz, 2H), 3.70-3.89 (complex, 2H), 4.14 (t, J=5.67 Hz,2H), 4.21 (t, J=4.15 Hz, 2H), 6.62-6.86 (complex, 6H), 7.03-7.12(complex, 4H), 7.18-7.30 (complex, 2H).

EXAMPLE 40

[0355]2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, sodium salt:

[0356] The title compound (0.11 g, 48%) was prepared as a white solidfrom 2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.22 g, 0.45mmol) obtained in example 39 by an analogous procedure to that describedin example 27.

[0357]¹H NMR (CDCl₃, 200 MHz): δ 1.02 (t, J=6.65 Hz, 3H), 2.75-2.92(complex, 4H), 3.39-3.58 (complex, 4H), 3.62 (bs, 2H), 4.04-4.20(complex, 4H), 6.49-6.82 (complex, 5H), 6.90-7.28 (complex, 6H),7.49-7.13 (complex, 1H).

EXAMPLE 41

[0358]3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxyphenyl]-2-ethoxypropanoicacid:

[0359] The title compound (0.75 g, 77%) was prepared as a white solidfrom methyl³-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate(1.0 g, 2.5 mmol) obtained in example 10 by a procedure analogous tothat described in example 26. mp: 90-03° C.

[0360]¹H NMR (CDCl₃, 200 MHz) : δ 1.18 (t, J=6.96 Hz, 3H), 2.88-3.13(complex, 2H), 3.41-3.63 (complex, 2H), 4.06 (dd, J=7.43 and 4.33 Hz,1H), 4.25-4.52 (complex, 4H), 4.61 (s, 2H), 6.80 (d, J=8.62 Hz, 2H),7.00-7.34 (complex, 6H). COOH proton is too broad to observe.

EXAMPLE 42

[0361]3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid, sodium salt:

[0362] The title compound (0.12 g, 56%) was prepared as a white solidfrom3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.2 g, 0.51 mmol) obtained in example 41 by an analogous procedureto that described in example 27.

[0363]¹H NMR (CDCl₃, 200 MHz): δ 0.99 (t, J=6.97 Hz, 3H), 2.61-2.80(complex, 2H), 3.32-3.57 (complex, 1H), 3.60-3.72 (complex, 1H),3.65-3.70 (complex, 1H), 4.18 (bs, 2H), 4.30 (bs, 2H), 4.68 (s, 2H),6.78 (d, J=8.4 Hz, 2H), 7.03-7.14 (complex, 5H), 7.42 (d, J=7.06 Hz,1H).

EXAMPLE 43

[0364]3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid:

[0365] The title compound (0.8 g, 69%) was prepared as a white solidfrom methyl3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate(1.2 g, 2.66 mmol) obtained in example 12 by an analogous procedure tothat described in example 26. mp: 102-104° C.

[0366]¹H NMR (CDCl₃, 200 MHz) : δ 1.15 (t, J=7.01 Hz, 3H), 3.06 (t,J=4.98 Hz, 2H), 3.08-3.63 (complex, 4H), 3.77-3.83 (complex, 4H), 4.15(dd, J=4.15 and 4.18 Hz, 1H), 4.28 (t, J=5.95 Hz, 2H), 6.59-6.79(complex, 2H), 6.96-7.36 (complex, 5H), 7.61-7.79 (complex, 3H). COOHproton is too broad to observe.

EXAMPLE 44

[0367]3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid, sodium salt:

[0368] The title compound (0.16 g, 76%) was prepared as a white solidfrom3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid (0.2 g, 0.457 mmol) obtained in example 43 by an analogousprocedure to that described in example 27. mp: 138-140° C.

[0369]¹H NMR (DMSO-d₆, 200 MHz): δ 0.98 (t, J=7.06 Hz, 3H), 2.72-2.90(complex, 1H), 2.92-3.21 (complex, 3H), 3.32-3.54 (complex, 2H),3.61-3.91 (complex, 5H), 4.28 (bs, 2H), 6.56 (t, J=7.00 Hz, 1H),6.73-7.00 (complex, 3H), 7.05-7.30 (complex, 2H), 7.38 (d, J=8.3 Hz,1H), 7.60-7.82 (complex, 3H).

EXAMPLE 45

[0370]3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid:

[0371] The title compound (0.06 g, 43%) was prepared as a brown syrupyliquid from ethyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate (0.15 g, 0.40mmol) obtained in example 13 by an analogous procedure to that describedin example 26.

[0372]¹H NMR (CDCl₃, 200 MHz): δ 2.85-3.19 (complex, 2H), 3.43 (t,J=4.15 Hz, 2H), 3.61 (t, J=5.49 Hz, 2H), 4.07 (t, J=5.40 Hz, 2H), 4.16(t, J=4.48 Hz, 2H), 4.45 (bs, 1H), 6.50-6.82 (complex, 6H), 7.08 (d,J=7.88 Hz, 2H). COOH and OH protons are too broad to observe.

EXAMPLE 46

[0373]3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid:

[0374] The title compound (0.7 g, 46%) was prepared as a white solidfrom ethyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate(1.7 g, 4.39 mmol) obtained in example 14 by a procedure analogous tothat described in example 26. mp: 74-76° C.

[0375]¹H NMR (CDCl₃, 200 MHz): δ 2.88-3.18 (complex, 4H), 3.69-3.79(complex, 4H), 4.15 (t, J=5.72 Hz, 2H), 4.45 (dd, J=6.73 and 4.79 Hz,1H), 4.51-4.97 (bs, D₂O exchangeable, 1H), 6.65-6.89 (complex, 4H),6.94-7.17 (complex, 4H), COOH proton is too broad to observe.

EXAMPLE 47

[0376]3-[4[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoicacid:

[0377] The title compound (0.15 g, 67%) was prepared as a thick liquidfrom ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate(0.24 g, 0.52 mmol) obtained in example 15 by a procedure analogous tothat described in example 26.

[0378]¹H NMR (CDCl₃, 200 MHz): δ 1.40-2.80 (br, 1H, D₂O exchangeable),2.99-3.18 (complex, 2H), 3.51 (t, J=4.34 Hz, 2H), 3.70 (t, J=5.82 Hz,2H), 4.13-4.24 (complex, 5H), 4.51 (d, J=17.0 Hz, 2H), 6.60-6.89(complex, 6H), 7.10-7.37 (complex, 7H).

EXAMPLE 48

[0379]3-14-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoicacid, sodium salt:

[0380] The title compound (0.1 g, 73%) was prepared as a cream coloredhygroscopic solid from3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoicacid (0.13 g, 0.30 mmol) obtained in example 47 by a procedure analogousto that described in example 27.

[0381]¹H NMR (DMSO-d₆, 200 MHz): 5 2.62-2.74 (complex, 1H), 2.89-2.98(complex, 1H), 3.48 (t, J=4.2 Hz, 2H), 3.67 (t, J=5.48 Hz, 2H),4.12-4.26 (complex, 5H), 4.65 (d, J=12.45 Hz, 2H), 6.45-6.84 (complex,6H), 7.12-7.25 (complex, 7H).

EXAMPLE 49

[0382]3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid:

[0383] The title compound (0.25 g, 67%) was prepared as a syrupy liquidfrom ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate(0.4 g, 0.93 mmol), obtained in example 16 by an analogous procedure tothat described in example 26.

[0384]¹H NMR (CDCl₃, 200 MHz): δ 0.87 (t, J=7.15 Hz, 3H), 1.25-1.40(complex, 2H), 1.49-1.66 (complex, 2H), 2.95-3.15 (complex, 2H),3.43-3.53 (complex, 4H), 3.68 (t, J=5.49 Hz, 2H), 4.00-4.12 (complex,1H), 4.14 (t, J=5.65 Hz, 2H), 4.22 (t, J=4.25 Hz, 2H), 6.60-6.89(complex, 6H), 7.12 (d, J=8.39 Hz, 2H). COOH proton is too broad toobserve.

EXAMPLE 50

[0385]3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid, sodium salt:

[0386] The title compound (0.12 g, 57%) was prepared as a hygroscopiccream colored solid from3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid (0.2 g, 0.5 mmol) obtained in example 49 by an analogous procedureto that described in example 27.

[0387]¹H NMR (DMSO-d6, 200 MHz) : δ 0.78 (t, J=7.06 Hz, 3H), 1.16-1.56(complex, 4H), 2.52-2.64 (complex, 1H), 2.79-2.87 (complex, 1H),2.99-3.18 (complex, 2H), 3.40 (bs, 2H), 3.66 (t, J=5.31 Hz, 2H), 4.10-4.25 (complex, 5H), 6.52-6.90 (complex, 6H), 7.12 (d, J=8.3Hz, 2H).

EXAMPLE 51

[0388]3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid:

[0389] The title compound (0.17 g, 60%) was prepared as a greenishliquid from ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoate(0.3 g, 0.65 mmol) obtained in example 17 by a procedure analogous tothat described in example 26.

[0390]¹H NMR (CDCl₃, 200 MHz): δ 0.86 (t, J=5.72 Hz, 3H), 1.25-1.33(complex, 4H), 1.41-1.75 (complex, 4H), 2.94-3.06 (complex, 2H),3.36-3.58 (complex, 4H), 3.68 (t, J=5.49 Hz, 2H), 4.01-4.06 (complex,1H), 4.14 (t, J=5.7 Hz, 2H), 4.22 (t, J=4.15 Hz, 2H), 6.71-7.08(complex, 6H), 7.12 (d, J=8.4 Hz, 2H). COOH proton is too broad toobserve.

EXAMPLE 52

[0391]3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid, sodium salt:

[0392] The title compound (0.1 g, 52%) was prepared as a whitehygroscopic solid from3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid (0.18 g, 0.42 mmol) obtained in example 51 by an analogousprocedure to that described in example 27.

[0393]¹H NMR (DMSO-d₆, 200 MHz): δ 0.82 (t, J=5.72 Hz, 3H), 1.10-1.45(complex, 8H), 2.75-2.96 (complex, 2H), 3.35-3.56 (complex, 4H), 3.67(t, J=5.3 Hz, 2H), 4.08-4.21 (complex, 5H), 6.50-6.82 (complex, 6H),7.12 (d, J=8.0 Hz, 2H).

EXAMPLE 53

[0394]3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid:

[0395] The title compound (0.1 g, 53%) was prepared as a colorlessliquid from methyl3-[4-[2-(2,3-dibydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(0.2 g, 0.461 mmol) obtained in example 19 by an analogous procedure tothat described in example 26.

[0396]¹H NMR (CDCl₃, 200 MHz): δ 2.40-2.80 (bs, 1H, D₂O exchangeable),3.22 (d, J=5.8 Hz, 2H), 3.49 (t, J=4.25 Hz, 2H), 3.67 (t, J=5.81 Hz,2H), 4.14 (t, J=5.81 Hz, 2H), 4.21 (t, J=4.16 Hz, 2H), 4.82 (t, J=5.9Hz, 1H), 6.61-7.02 (complex, 8H), 7.17-7.30 (complex, 5H).

EXAMPLE 54

[0397]3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid:

[0398] The title compound (0.2 g, 51%) was prepared as a gummy solidfrom methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(0.4 g, 0.9 mmol) obtained in example 21 by a procedure analogous tothat described in example 26.

[0399]¹H NMR (CDCl₃, 200 MHz) : δ 3.02 (t, J=5.0 Hz, 2H), 3.22 (d,J=6.25 Hz, 2H), 3.68-3.78 (complex, 4H), 4.14 (t, J=5.81 Hz, 2H), 4.50(t, J=6.19 Hz, 1H), 4.90-5.40 (b, 1H, D20 exchangeable), 6.58-6.86(complex, 7H), 6.94 7.07 (complex, 2H), 7.18-7.29 (complex, 4H).

EXAMPLE 55

[0400]3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid, sodium salt:

[0401] The title compound (0.05 g, 48%) was prepared as a hygroscopicsolid from3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid (0.1 g, 0.24 mmol) obtained in example 53 by a procedure analogousto that described in example 27.

[0402]¹H NMR (DMSO-d₆, 200 MHz): δ 2.81-3.09 (complex, 2H), 3.42 (bs,2H), 3.65 (t, J=4.5 Hz, 2H), 4.12 (bs, 4H), 4.22-4.32 (complex, 1H),6.50-6.92 (complex, 8H), 7.10-7.33 (complex, 5H).

EXAMPLE 56

[0403] Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate:

[0404] The title compound (0.27 g, 87%) was prepared as a syrupy liquidfrom methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(0.3 g, 0.69 mmol) obtained in example 19 by an analogous procedure tothat described in example 7.

[0405]¹H NMR (CDCl₃, 200 MHz) : δ 1.39 (s, 3H), 3.09, 3.26 (lH each, 2d,J=13.7 Hz each), 3.51 (t, J=4.3 Hz, 2H), 3.66-3.73 (complex, 5H), 4.15(t, J=5.5 Hz, 2H), 4.22 (t, J=4.24 Hz, 2H), 6.61-7.01 (complex, 9 H),7.12-7.22 (complex, 4H).

EXAMPLE 57

[0406]2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid:

[0407] The title compound (0.13 g, 50%) was prepared as a pale yellowhygroscopic solid from methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(0.27 g, 0.60 mmol) obtained in example 56 by a procedure analogous tothat described in example 26.

[0408]¹H NMR (CDCl₃, 200 MHz) : δ 1.42 (s, 3H), 3.12, 3.29 (1H each, 2d,J=14.1 Hz each), 3.50 (t, J=4.5 Hz, 2H), 3.69 (t, J=5.6 Hz, 2H), 4.16(t, J=5.81 Hz, 2H), 4.22 (t, J=4.5 Hz, 2H), 6.62-7.17 (complex, 9H),7.21-7.30 (complex, 4H). COOH proton is too broad to observe.

EXAMPLE 58

[0409]2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid, sodium salt:

[0410] The title compound (0.055 g, 46%) was prepared as a hygroscopicpale yellow powder from2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid (0.13 g, 0.28 mmol) obtained in example 57 by a procedure analogousto that described in example 27.

[0411]¹H NMR (CDCl₃, 200 MHz) : δ 1.15 (s, 3H), 2.99-3.21 (complex, 2H),3.47 (bs, 2H), 3.67 (bs, 2H), 4.14 (bs, 4H), 6.53-6.9 (complex, 9H),7.08-7.30 (complex, 4H).

EXAMPLE 59

[0412] Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate:

[0413] The title compound (0.96 g, 93%) was prepared as a pale yellowliquid from methyl3-[4-[2-(2,3-dihydo-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(1.0 g, 2.22 mmol) obtained in example 21 by an analogous procedure tothat described in example 7.

[0414]¹H NMR (CDCl₃, 200 MHz) : δ 1.40 (s, 3H), 3.03 (t, J=4.9 Hz, 2H),3.09, 3.27 (1H each, 2d, J=13.7 Hz each), 3.70-3.85 (complex, 7H), 4.16(t, 3 5.81 Hz, 2H), 6.60-6.89 (complex, 6H), 6.96-7.30 (complex, 7H).

EXAMPLE 60

[0415]2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid:

[0416] The title compound (0.6 g, 65%) was prepared as a syrupy liquidfrom methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate(0.96 g, 2.00 mmol) obtained in example 59 by an analogous procedure tothat described in example 26.

[0417]¹H NMR (CDCl₃, 200 MHz): δ 1.42 (s, 3H), 3.03 (t, J=5.0 Hz, 2H),3.12, 3.30 (1H each, 2d, J=13.8 Hz each), 3.70-3.80 (complex, 4H), 4.15(t, J=5.5 Hz, 2H), 6.58-7.08 (complex, 8H). 7.18-7.30 (complex, 5H),COOH proton is too broad to observe.

EXAMPLE 61

[0418] 4-Nitrophenyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate:

[0419] The title compound (0.15 g, 38%) was prepared as a yellow liquidfrom3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid (0.3 g, 0.77 mmol) obtained in example 29 and 4-nitrophenol by ananalogous procedure to that described in example 32.

[0420]¹H NMR (CDCl₃, 200 MHz): δ 1.24 (t, J=6.92 Hz, 3H), 3.04 (t,J=5.16 Hz, 2H), 3.12 (d, J=6.63 Hz, 2H), 3.46-3.65 (complex, 1H),3.70-3.86 (complex, 5H), 4.16 (t, J=5.23 Hz, 5 2H), 4.26 (t, J=5.5 Hz,1H), 6.62-6.74 (complex, 2H), 6.84 (d, J=8.62 Hz, 2H), 6.94-7.22(complex, 6H), 8.23 (d, J=9.0 Hz, 2H).

EXAMPLE 62

[0421]3-[4-(4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoicacid:

[0422] The title compound (0.4 g, 57%) was prepared as a syrupy liquidfrom methyl3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate(0.8 g, 2.16 mmol) obtained in example 25 by an analogous procedure tothat described in example 26.

[0423]¹H NMR (CDCl₃, 200 MHz): δ 1.17 (t, J=7.0 Hz, 3H), 2.99-3.13(complex, 2H), 3.31-3.65 (complex, 4H), 4.01-4.24 (complex, 3H), 4.45(d, J=3.4 Hz, 2H), 4.52-4.59 (complex, 1H), 6.62-6.68 (complex, 6H),7.14 (d, J=8.6 Hz, 2H), 7.27 (s, 5H). COOH proton is too broad toobserve.

EXAMPLE 63

[0424]3-[4-(4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoicacid, sodium salt:

[0425] The title compound (0.15 g, 75%) was prepared as a colorlesshygroscopic solid from3-[4-(4benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoicacid (0.2 g, 0.44 mmol) obtained in example 62 by an analogous procedureto that described in example 27.

[0426]¹H NMR (DMSO-d₆, 200 MHz): δ 0.99 (t, J=6.97 Hz, 3H), 2.60-2.90(complex, 2H), 3.30-3.65 (complex, 5H), 4.16 (d, J=5.0 Hz, 2H),4.40-4.65 (complex, 3H), 6.55-6.89 (complex, 6H), 7.14 (d, J=8.5 Hz,2H), 7.32 (s, 5H).

EXAMPLE 64

[0427]4Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate:

[0428] The title compound (0.6 g, 100%) was prepared as a dark brownliquid from3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoicacid (0.5 g, 1.34 mmol) obtained in example 62 and 4-nitro phenol by aprocedure analogous to that described in example 32.

[0429]¹H NMR (CDCl₃, 200 MHz): δ 1.25 (t, J=7.0 Hz, 3H), 3.14 (d, J=6.6Hz, 2H), 3.33-3.55 (complex, 3H), 3.69-3.77 (complex, 1H), 4.05-4.31(complex, 3H), 4.46 (d, J=3.4 Hz, 2H), 4.55-4.61 (complex, 1H),6.63-6.68 (complex, 6H), 7.11-7.28 (complex, 7H), 7.52 (d, J=7.6 Hz,2H), 8.23 (d, J=9.0 Hz, 2H).

[0430] The compounds of the present invention lowered random blood sugarlevel, triglyceride, total cholesterol, LDL, VLDL and increased HDL.This was demonstrated by in vitro as well as in vivo animal experiments.

Demonstration of Efficacy of Compounds

[0431] A) In vitro:

[0432] a) Determination of hPPARα activity:

[0433] Ligand binding domain of hPPARcα was fused to DNA binding domainof Yeast transcription factor GAL4 in eucaryotic expression vector.Using superfect (Qiagen, Germany) as transfecting reagent HEK-293 cellswere transfected with this plasmid and a reporter plasmid harboring theluciferase gene driven by a GAL4 specific promoter. Compound was addedat different concentrations after 42 hrs of transfection and incubatedovernight. Luciferase activity as a function of compoundbinding/activation capacity of PPARγ1 was measured using Packard Luclitekit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, PeterBroag and Melvyn Hollis. Gene. 1992. 118: 137 -141; SuperfectTransfection Reagent Handbook. February, 1997. Qiagen, Germany).

[0434] b) Determination of hPPARγ activity:

[0435] Ligand binding domain of hPPARγ1 was fused to DNA binding domainof Yeast transcription factor GAL4 in eucaryotic expression vector.Using lipofectamine (Gibco BRL, USA) as transfecting reagent HEK-293cells were transfected with this plasmid and a reporter plasmidharboring the luciferase gene driven by a GAL4 specific promoter.Compound was added at 1 μM concentration after 48 brs of transfectionand incubated overnight. Luciferase activity as a function of drugbinding/activation capacity of PPARγ1 was measured using Packard Luclitekit (Packard, USA) in Packard Top Count (Ivan Sadowski, Brendan Bell,Peter Broag and Melvyn Hollis. Gene. 1992. 118: 137 -141; Guide toEukaryotic Transfections with Cationic Lipid Reagents. LifeTechnologies, GIBCO BRL, USA).

[0436] c) Determination of HMG CoA reductase inhibition activity:

[0437] Liver microsome bound reductase was prepared from 2%cholestyramine fed rats at mid-dark cycle. Spectrophotometric assayswere carried out in 100 mM KH₂PO₄, 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMGCoA and 125 μg of liver microsomal enzyme. Total reaction mixture volumewas kept as 1 ml. Reaction was started by addition of HMG CoA. Reactionmixture was incubated at 37° C. for 30 min and decrease in absorbance at340 nm was recorded. Reaction mixture without substrate was used asblank (Goldstein, J. L and Brown, M. S. Progress in understanding theLDL receptor and HMG CoA reductase, two membrane proteins that regulatethe plasma cholesterol. J. Lipid Res. 1984, 25: 1450-1461). The testcompounds inhibited the HMG CoA reductase enzyme.

[0438] B) In vivo:

[0439] a) Efficacy in genetic models:

[0440] Mutation in colonies of laboratory animals and differentsensitivities to dietary regimens have made the development of animalmodels with non-insulin dependent diabetes and hyperlipidemia associatedwith obesity and insulin resistance possible. Genetic models such asdb/db and ob/ob (Diabetes, (1982) 31(1): 1- 6) mice and zucker fa/farats have been developed by the various laboratories for understandingthe pathophysiology of disease and testing the efficacy of newantidiabetic compounds (Diabetes, (1983) 32: 830-838; Annu. Rep. SankyoRes. Lab. (1994). 46:1-57). The homozygous animals, C57 BL/KsJ-db/dbmice developed by Jackson Laboratory, U.S., are obese, hyperglycemic,hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85:962-967), whereas heterozygous are lean and normoglycemic. In db/dbmodel, mouse progressively develops insulinopenia with age, a featurecommonly observed in late stages of human type II diabetes when bloodsugar levels are insufficiently controlled. The state of pancreas andits course vary according to the models. Since this model resembles thatof type II diabetes mellitus, the compounds of the present inventionwere tested for blood sugar and triglycerides lowering activities.

[0441] Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having bodyweight range of 35 to 60 grams, bred at Dr. Reddy's Research Foundation(DRF) animal house, were used in the experiment. The mice were providedwith standard feed (National Institute of Nutrition (NIN), Hyderabad,India) and acidified water, ad libitum. The animals having more than 350mg/dl blood sugar were used for testing. The number of animals in eachgroup was 4.

[0442] Test compounds were suspended on 0.25% carboxymethyl celluloseand administered to test group at a dose of 0.1 mg to 30 mg/kg throughoral gavage daily for 6 days. The control group received vehicle (dose10 ml/kg). On 6th day the blood samples were collected one hour afteradministration of test compounds/vehicle for assessing the biologicalactivity.

[0443] The random blood sugar and triglyceride levels were measured bycollecting blood (100 μl) through orbital sinus, using heparinisedcapillary in tubes containing EDTA which was centrifuged to obtainplasma. The plasma glucose and triglyceride levels were measuredspectrometrically, by glucose oxidase and glycerol-3-PO₄oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits,Hyderabad, India) methods respectively.

[0444] The blood sugar and triglycerides lowering activities of the testcompound was calculated according to the formula.

[0445] No adverse effects were observed for any of the mentionedcompounds of invention in the above test. Reduction in BloodTriglyceride Compound Dose (mg/kg) Glucose Level (%) Lowering (%)Example 41 3 53 27 Example 50 3 45 23 Example 44 10 47 74

[0446] The ob/ob mice were obtained at 5 weeks of age from Bomholtgard,Demark and were used at 8 weeks of age. Zucker fa/fa fatty rats wereobtained from IffaCredo, France at 10 weeks of age and were used at 13weeks of age. The animals were maintained under 12 hour light and darkcycle at 25±1° C. Animals were given standard laboratory chow (NIN,Hyderabad, India) and water, ad libitum (Fujiwara, T., Yoshioka, S.,Yoshioka, T., Ushiyama, I and Horikoshi, H. Characterization of new oralantidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fattyrats. Diabetes. 1988. 37: 1549-1558).

[0447] The test compounds were administered at 0.1 to 30 mg/kg/day dosefor 9 days. The control animals received the vehicle (0.25%carboxymethylcellulose, dose 10 ml/kg) through oral gavage.

[0448] The blood samples were collected in fed state 1 hour after drugadministration on 0 and 9 day of treatment. The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifugation, plasma sample was separated fortriglyceride, glucose, free fatty acid, total cholesterol and insulinestimations. Measurement of plasma triglyceride, glucose, totalcholesterol were done using commercial kits (Dr. Reddy's Laboratory,Diagnostic Division, India). The plasma free fatty acid was measuredusing a commercial kit from Boehringer Mannheim, Germany. The plasmainsulin was measured using a RIA kit (BARC, India). The reduction ofvarious parameters examined are calculated according to the formulagiven below.

[0449] In ob/ob mice oral glucose tolerance test was performed after 9days treatment. Mice were fasted for 5 hrs and challenged with 3 gm/kgof glucose orally. The blood samples were collected at 0, 15, 30, 60 and120 min for estimation of plasma glucose levels.

[0450] The experimental results from the db/db mice, ob/ob mice, Zuckerfa/fa rats suggest that the novel compounds of the present inventionalso possess therapeutic utility as a prophylactic or regular treatmentfor diabetes, obesity, cardiovascular disorders such as hypertension,hyperlipidaemia and other diseases; as it is known from the literaturethat such diseases are interrelated to each other.

[0451] Blood glucose level and triglycerides are also lowered at dosesgreater than 10 mg/kg. Normally, the quantum of reduction is dosedependent and plateaus at certain dose.

[0452] b) Plasma triglyceride and Cholesterol lowering activity inhypercholesterolemic rat models:

[0453] Male Sprague Dawley rats (NIN stock) were bred in DRF animalhouse. Animals were maintained under 12 hour light and dark cycle at25±1° C. Rats of 180-200 gram body weight range were used for theexperiment. Animals were made hypercholesterolemic by feeding 2%cholesterol and 1% sodium cholate mixed with standard laboratory chow[National Institute of Nutrition (NIN), Hyderabad, India] for 6 days.Throughout the experimental period the animals were maintained on thesame diet (Petit, D., Bonnefis, M. T., Rey, C and Infante, R. Effects ofciprofibrate on liver lipids and lipoprotein synthesis in normo- andhyperlipidemic rats. Atherosclerosis. 1988. 74: 215-225).

[0454] The test compounds were administered orally at a dose 0.1 to 30mg/kg/day for 3 days. Control group was treated with vehicle alone(0.25% Carboxymethylcellulose; dose 10 ml/kg).

[0455] The blood samples were collected in fed state 1 hour after drugadministration on 0 and 3 day of compound treatment. The blood wascollected from the retro-orbital sinus through heparinised capillary inEDTA containing tubes. After centrifugation, plasma sample was separatedfor total cholesterol, HDL and triglyceride estimations. Measurement ofplasma triglyceride, total cholesterol and HDL were done usingcommercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India).LDL and VLDL cholesterol were calculated from the data obtained fortotal cholesterol, HDL and triglyceride. The reduction of variousparameters examined are calculated according to the formula. TotalExample Dose Triglyceride Cholesterol No. mg/kg (%) ↓ (%) ↓ HDL (%) ↑LDL (%) ↓ VLDL(%) ↓ Example 1 43 57 37 58 79 27 Example 1 50 42 46 44 5344

[0456] c) Plasma triglyceride and total cholesterol lowering activity inSwiss albino mice and Guinea pigs:

[0457] Male Swiss albino mice (SAM) and male Guinea pigs were obtainedfrom NIN and housed in DRF animal house. All these animals weremaintained under 12 hour light and dark cycle at 25±1° C. Animals weregiven standard laboratory chow (NIN, Hyderabad, India) and water, adlibitum. SAM of 20-25 g body weight range and Guinea pigs of 500-700 gbody weight range were used (Oliver, P., Plancke, M. O., Marzin, D.,Clavey, V., Sauzieres, J and Fruchart, J. C. Effects of fenofibrate,gemfibrozil and nicotinic acid on plasma lipoprotein levels in normaland hyperlipidemic mice. Atherosclerosis. 1988. 70: 107-114).

[0458] The test compounds were administered orally to Swiss albino miceat 0.3 to 30 mg/kg/day dose for 6 days. Control mice were treated withvehicle (0.25% Carboxymethylcellulose; dose 10 ml/kg). The testcompounds were administered orally to Guinea pigs at 0.3 to 30 mg/kg/daydose for 6 days. Control animals were treated with vehicle (0.25%Carboxymethylcellulose; dose 5 ml/kg).

[0459] The blood samples were collected in fed state 1 hour after drugadministration on 0 and 6 day of treatment. The blood was collected fromthe retro-orbital sinus through heparinised capillary in EDTA containingtubes. After centrifugation, plasma sample was separated fortriglyceride and total cholesterol (Wieland, O. Methods of Enzymaticanalysis. Bergenneyer, H. O., Ed., 1963. 211-214; Trinder, P. Ann. Clin.Biochem. 1969. 6:24-27). Measurement of plasma triglyceride, totalcholesterol and HDL were done using commercial kits (Dr. Reddy'sDiagnostic Division, Hyderabad, India). Triglyceride Lowering CompoundDose (mg/kg) (%) Example 33 3 55 Example 41 10 54 Example 43 3 49Example 63 3 57

[0460] c) Body weight reducing effect in cholesterol fed hamsters:

[0461] Male Syrian Hamsters were procured from NIN, Hyderabad, India.Animals were housed at DRF animal house under 12 hour light and darkcycle at 25±1° C. with free access to food and water. Animals weremaintained with 1% cholesterol containing standard laboratory chow (NIN)from the day of treatment.

[0462] The test compounds were administered orally at 1 to 30 mg/kg/daydose for 15 days. Control group animals were treated with vehicle (MillQ water, dose 10 ml/kg/day). Body weights were measured on every ₃rdday. Dose Body weight Example No. (mg/kg/day) Reduction (%) Example 2710 12 Example 30 10 18

[0463] Formulae for calculation:

[0464] 1. Percent reduction in Blood sugar/triglycerides/totalcholesterol/body weight were calculated according to the formula:${{Percet}\quad {reduction}\quad (\%)} = {1 - {\frac{{TT}/{OT}}{{TC}/{OC}} \times 100}}$

[0465] OC=Zero day control group value

[0466] OT=Zero day treated group value

[0467] TC=Test day control group value

[0468] TT=Test day treated group value

[0469] 2. LDL and VLDL cholesterol levels were calculated according tothe formula:${{LDL}\quad {cholesterol}\quad {in}\quad {{mg}/{dl}}} = {{{Total}\quad {cholesterol}} - {{HDL}\quad {cholesterol}} - \frac{triglyceride}{5}}$

[0470] VLDL cholesterol in mg/dl=Total cholesterol−HDL cholesterol−LDLcholesterol

We claim
 1. A compound of formula (I)

its derivatives, its analogs, its tautomeric forms, its stereoisomers,its polymorphs, its pharmaceutically acceptable salts, itspharmaceutically acceptable solvates, wherein the groups R¹, R², R³, R⁴,and the groups R⁵ and R⁶ when attached to a carbon atom, may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor optionally substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;one or both of R⁵ and R⁶ may represent an oxo group when attached to acarbon atom; R⁵ and R⁶ when attached to a nitrogen atom representshydrogen, hydroxy, formyl or optionally substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino,acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy,aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,or sulfonic acid derivatives; X represents a heteroatom selected fromoxygen, sulfur or NR¹¹ where R¹¹ is selected from hydrogen, oroptionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl group; Arrepresents an optionally substituted divalent single or fused aromaticor heterocyclic group; R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, optionally substituted aralkyl group or forms abond together with adjacent group R⁸; R⁸ represents hydrogen, hydroxy,alkoxy, halogen, lower alkyl group, acyl, or optionally substitutedaralkyl or R⁸ forms a bond together with R⁷; R⁹ represents hydrogen, oroptionally substituted groups selected from alkyl, cycloalkyl, aryl,aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,or heteroaralkyl groups; R¹⁰ represents hydrogen or optionallysubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl, or heteroaralkyl groups; Y represents oxygenor NR¹², where R¹² represents hydrogen, alkyl, aryl, hydroxyalkyl,aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl groups; R¹⁰ and R¹²together may form a 5 or 6 membered cyclic structure containing carbonatoms, which may optionally contain one or more heteroatoms selectedfrom oxygen, sulfur or nitrogen; the linking group represented by-(CH₂)_(n)-(O)_(m)- may be attached either through a nitrogen atom or acarbon atom; n is an integer ranging from 1-4 and m is an integer 0or
 1. 2. A compound according to claim 1, wherein when the groupsrepresented by R¹-R⁴ and the groups R⁵ and R⁶ when attached to a carbonatom are substituted, the substituents are selected from halogen,hydroxy, or nitro or optionally substituted groups selected from alkyl,cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl,heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl,amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl,alkylamino, alkoxyalkyl, alkylthio, thioalkyl, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives.
 3. A compoundaccording to claim 1, wherein when the groups R⁵ and R⁶ attached tonitrogen are substituted, the substituents are selected from halogenatoms, hydroxy, acyl, acyloxy, or amino groups.
 4. A compound accordingto claim 1, wherein Ar represents optionally substituted divalentphenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl,dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl,indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, orbenzoxazolyl groups.
 5. A compound according to claim 1, wherein thesubstituents on the group represented by R⁹ are selected from halogen,hydroxy, or nitro or optionally substituted groups selected from alkyl,cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl,heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl,amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl,alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid orits derivatives, or sulfonic acid or its derivatives.
 6. A process forthe preparation of compound of formula (I)

its derivatives, its analogs, its tautomeric forms, its stereoisomers,its polymorphs, its pharmaceutically acceptable salts, itspharmaceutically acceptable solvates, wherein the groups R¹, R², R³, R⁴,and the groups R⁵ and R⁶ when attached to a carbon atom, may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor optionally substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;one or both of R⁵ and R⁶ may represent an oxo group when attached to acarbon atom; R⁵ and R⁶ when attached to nitrogen atom representshydrogen, hydroxy, formyl or optionally substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino,acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy,aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,or sulfonic acid derivatives; X represents a heteroatom selected fromoxygen, sulfur or NR¹¹ where R¹¹ is selected from hydrogen, oroptionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl group; Arrepresents an optionally substituted divalent single or fused aromaticor heterocyclic group; R⁷ and R⁸ together represent a bond; R⁹represents hydrogen, or optionally substituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl,heterocyclyl, heteroaryl, or heteroaralkyl groups; R¹⁰ representshydrogen or optionally substituted groups selected from alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkylgroup; Y represents oxygen; the linking group represented by-(CH₂)_(n)-(O)_(m)- may be attached either through nitrogen atom orcarbon atom; n is an integer ranging from 1-4 and m is an integer 0 or1, which comprises: a) reacting a compound of formula (IIIa)

where all symbols are as defined above with a compound of formula (IIIb)

where R⁹ and R¹⁰ are as defined above and R¹⁴ represents (C₁—C₆)alkyl,to yield compound of formula (I) defined above; b) reacting a compoundof formula (IIIc)

where all symbols are as defined above with a compound of formula (IIId)

where R⁷ and R⁸ together represent a bond and all symbols are as definedabove and L¹ is a leaving group to produce a compound of formula (I)defined above; c) reacting a compound of formula (IIIe)

where all symbols are as defined above with a compound of formula (IIIf)

where R⁹ R¹⁰ and are as defined above to produce a compound of theformula (I); d) reacting a compound of formula (IIIa)

where all other symbols are as defined above with a compound of formula(IIIg)

where R⁸, R⁹, and R¹⁰ are as defined above to yield a compound offormula (I) as defined above after dehydration; e) reacting a compoundof formula (IIIh)

where all symbols are as defined earlier and L¹ represents a leavinggroup, with compound of formula (IIIi)

where R⁷ and R⁸ together represent a bond and R⁹, R¹⁰ and Ar are asdefined earlier to produce a compound of the formula (I) where mrepresents an integer 1 and all other symbols are as defined above; f)reacting a compound of formula (IIIj)

where all symbols are as defined above with a compound of formula (IIIi)

where R⁷ and R⁸ together represent a bond and R⁹, R¹⁰ and Ar are asdefined above to produce a compound of formula (I) where m represents aninteger 1 and all other symbols are as defined above; and optionally, g)converting the compounds of formula (I) obtained in any of the processesdescribed above into pharmaceutically acceptable salts orpharmaceutically acceptable solvates.
 7. A process for the preparationof compound of formula (I)

its derivatives, its analogs, its tautomeric forms, its stereoisomers,its polymorphs, its pharmaceutically acceptable salts, itspharmaceutically acceptable solvates, wherein the groups R¹, R², R³, R⁴,and the groups R⁵ and R⁶ when attached to a carbon atom, may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor optionally substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;one or both of R⁵ and R⁶ may represent an oxo group when attached to acarbon atom; R⁵ and R⁶ when attached to a nitrogen atom representshydrogen, hydroxy, formyl or optionally substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino,acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy,aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,or sulfonic acid derivatives; X represents a heteroatom selected fromoxygen, sulfur or NR¹¹ where R¹¹ is selected from hydrogen, oroptionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Arrepresents an optionally substituted divalent single or fused aromaticor heterocyclic group; R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, or optionally substituted aralkyl group; R⁸represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl,or optionally substituted aralkyl; R⁹ represents hydrogen, or optionallysubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkylgroups; R¹⁰ represents hydrogen or optionally substituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl, or heteroaralkyl groups; Y represents oxygen; the linkinggroup represented by -(CH₂)_(n)—(O)_(m)- may be attached either througha nitrogen atom or a carbon atom; n is an integer ranging from 1-4 and mis an integer 0 or 1, which comprises: a) reducing a compound of formula(IVa)

which represents a compound of formula (I) where R⁷ and R⁸ togetherrepresent a bond and Y represents an oxygen atom and all other symbolsare as defined above, prepared according to any of the processes claimedin claim 6, to yield a compound of the formula (I) where R⁷ and R⁸ eachrepresent hydrogen atom and all symbols are as defined above; b)reacting a compound of formula (IVb)

where all symbols are as defined above and L² is a leaving group with analcohol of formula (IVc), R⁹-OH   (IVc) where R⁹ represents optionallysubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkylgroups produce a compound of the formula (s) defined above; c) reactinga compound of formula (IIIh)

where all symbols are as defined above and L¹ is a leaving group with acompound of formula (IIIi)

where all symbols are as defined above to produce a compound of theformula (I) where m represents an integer 1 and all other symbols are asdefined above; d) reacting a compound of formula (IIIj)

where all symbols are as defined above with a compound of formula (IIIi)

where all symbols are as defined above to produce a compound of formula(I) where m represents an integer 1 and all other symbols are as definedabove; e) reacting a compound of formula (IVd)

which represents a compound of formula (I) where R⁹ represents ahydrogen atom and all other symbols are as defined above with a compoundof formula (IVe) R⁹-L² (IVe) where R⁹ represents optionally substitutedgroups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl,acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups and L² is ahalogen atom to produce a compound of formula (I) defined above; f)reacting a compound of the formula (IIIa)

where all symbols are as defined above with a compound of formula (IIIg)

where R^(8,) R⁹, R¹⁰ are as defined above to produce a compound offormula (I) after dehydroxylation; g) reacting a compound of formula(IIIc)

where all symbols are as defined above with a compound of formula (IIId)

where L¹ is a leaving group and all other symbols are as defined aboveto produce a compound of formula (I) defined above; h) converting acompound of formula (IVf)

where all symbols are as defined above to a compound of formula (I)defined above; i) reacting a compound of formula (IVg)

where all symbols are as defined above with a compound of formula (IVc)R⁹-OH (IVc) where R⁹ represents optionally substituted groups selectedfrom alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl,heterocyclyl, heteroaryl, or heteroaralkyl groups to produce a compoundof formula (I), optionally; j) resolving the compound of formula (I)obtained in any of the processes described above into its stereoisomers,and optionally; k) converting the compounds of formula (I) or itsstereoisomers obtained in any of the processes described above intopharmaceutically acceptable salts or pharmaceutically acceptablesolvates.
 8. A process for the preparation of compound of formula (I)

its derivatives, its analogs, its tautomeric forms, its stereoisomers,its polymorphs, its pharmaceutically acceptable salts, itspharmaceutically acceptable solvates, wherein the groups R¹, R², R³, R⁴,and the groups R⁵ and R⁶ when attached to a carbon atom, may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor optionally substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;or one or both of R⁵ and R⁶ may represent an oxo group when attached toa carbon atom; R⁵ and R⁶ when attached to a nitrogen atom representshydrogen, hydroxy, formyl or optionally substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino,acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy,aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,or sulfonic acid derivatives; X represents a heteroatom selected fromoxygen, sulfur or NR¹¹ where R¹¹ is selected from hydrogen, oroptionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Arrepresents an optionally substituted divalent single or fused aromaticor heterocyclic group; R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, or optionally substituted aralkyl group or forms abond together with the adjacent group R⁸; R⁸ represents hydrogen,hydroxy, alkoxy, halogen, lower alkyl group, acyl, or optionallysubstituted aralkyl or R⁸ forms a bond together with R⁷; R⁹ representshydrogen, or optionally substituted groups selected from alkyl,cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,or heteroaralkyl groups; R¹⁰ represents hydrogen or optionallysubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl, or heteroaralkyl groups; Y represents NR¹²,where R¹² represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl,heterocyclyl, heteroaryl, or heteroaralkyl group; R¹⁰ and R¹² togethermay form a 5 or 6 membered cyclic structure containing carbon atoms,which may optionally contain one or more heteroatoms selected fromoxygen, sulfur or nitrogen; the linking group represented by-(CH₂)_(n)-(O)_(m)- may be attached either through a nitrogen atom or acarbon atom; n is an integer ranging from 1-4 and m is an integer 0 or1, which comprises: a) reacting a compound of formula (I)

where all symbols are as defined above and Y represents oxygen, YR¹⁰represents a halogen atom, or COYR¹⁰ represents a mixed anhydride groupwith appropriate amines of the formula NHR¹⁰R¹², where R¹⁰ and R¹² areas defined earlier and, optionally; b) resolving the compound of formula(I) obtained above into stereoisomers, optionally; c) converting thecompounds of formula (I) obtained above into pharmaceutically acceptablesalts or pharmaceutically acceptable solvates.
 9. A compound of formula(I)

its derivatives, its analogs, its tautomeric forms, its stereoisomers,its polymorphs, its pharmaceutically acceptable salts, itspharmaceutically acceptable solvates, wherein the groups R¹, R², R³, R⁴,and the groups R⁵ and R⁶ when attached to a carbon atom, may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor optionally substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;one or both of R⁵ and R⁶ may represent an oxo group when attached to acarbon atom; R⁵ and R⁶ when attached to nitrogen atom representshydrogen, hydroxy, formyl or optionally substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino,acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy,aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,or sulfonic acid derivatives; X represents a heteroatom selected fromoxygen, sulfur or NR¹¹ where R¹¹ is selected from hydrogen, oroptionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Arrepresents an optionally substituted divalent single or fused aromaticor heterocyclic group; R⁷ and R⁸ together represent a bond; R⁹represents hydrogen, or optionally substituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl,aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl,heterocyclyl, heteroaryl, or heteroaralkyl groups; R¹⁰ representshydrogen or optionally substituted groups selected from alkyl,cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkylgroups; Y represents oxygen; the linking group represented by-(CH₂)_(n)-(O)_(m)- may be attached either through a nitrogen atom or acarbon atom; n is an integer ranging from 1-4 and m is an integer 0 or1, prepared according to the process of claim
 6. 10. A compound offormula (I)

its derivatives, its analogs, its tautomeric forms, its stereoisomers,its polymorphs, its pharmaceutically acceptable salts, itspharmaceutically acceptable solvates, wherein the groups R¹, R², R³, R⁴,and the groups R⁵ and R⁶ when attached to a carbon atom, may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor optionally substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;one or both of R⁵ and R⁶ may represent an oxo group when attached to acarbon atom; R⁵ and R⁶ when attached to a nitrogen atom representshydrogen, hydroxy, formyl or optionally substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino,acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy,aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,or sulfonic acid derivatives; X represents a heteroatom selected fromoxygen, sulfur or NR¹¹ where R¹¹ is selected from hydrogen, oroptionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Arrepresents an optionally substituted divalent single or fused aromaticor heterocyclic group; R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, optionally substituted aralkyl group; R⁸represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl,or optionally substituted aralkyl; R⁹ represents hydrogen, or optionallysubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkylgroups; R¹⁰ represents hydrogen or optionally substituted groupsselected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl, or heteroaralkyl groups; Y represents oxygen; the linkinggroup represented by -(CH₂)_(n)-(O)_(m)- may be attached either througha 20 nitrogen atom or a carbon atom; n is an integer ranging from 1-4and m is an integer 0 or 1, prepared according to the process of claim7.
 11. A compound of formula (I)

its derivatives, its analogs, its tautomeric forms, its stereoisomers,its polymorphs, its pharmaceutically acceptable salts, itspharmaceutically acceptable solvates, wherein the groups R¹, R², R³, R⁴,and the groups R⁵ and R⁶ when attached to a carbon atom, may be same ordifferent and represent hydrogen, halogen, hydroxy, nitro, cyano, formylor optionally substituted groups selected from alkyl, cycloalkyl,alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl,heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy,hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino,aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl,alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino,carboxylic acid or its derivatives, or sulfonic acid or its derivatives;one or both of R⁵ and R⁶ may represent an oxo group when attached to acarbon atom; R⁵ and R⁶ when attached to a nitrogen atom representshydrogen, hydroxy, formyl or optionally substituted groups selected fromalkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl,heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino,acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy,aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl,aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,or sulfopic acid derivatives; X represents a heteroatom selected fromoxygen, sulfur or NR¹¹ where R¹¹ is selected from hydrogen, oroptionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl groups; Arrepresents an optionally substituted divalent single or fused aromaticor heterocyclic group; R⁷ represents hydrogen atom, hydroxy, alkoxy,halogen, lower alkyl, or optionally substituted aralkyl group or forms abond together with the adjacent group R⁸; R⁸ represents hydrogen,hydroxy, alkoxy, halogen, lower alkyl group, acyl, or optionallysubstituted aralkyl or R⁸ forms a bond together with R⁷; R⁹ representshydrogen, or optionally substituted groups selected from alkyl,cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,or heteroaralkyl group; R¹⁰ represents hydrogen or optionallysubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl, heteroaryl, or heteroaralkyl groups; Y represents NR¹²where R¹² represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl,heterocyclyl, heteroaryl, or heteroaralkyl groups; R¹⁰ and R¹² togethermay form a 5 or 6membered cyclic structure containing carbon atoms,which may optionally contain one or more heteroatoms selected fromoxygen, sulfur or nitrogen; the linking group represented by-(CH₂)_(n)-(O)_(m)- may be attached either through a nitrogen atom or acarbon atom; n is an integer ranging from 1-4 and m is an integer 0 or1, prepared according to the process of claim
 8. 12. An intermediate offormula (IVf)

where the groups R¹, R², R³, R⁴, and the groups R⁵ and R⁶ when attachedto a carbon atom, may be same or different and represent hydrogen,halogen, hydroxy, nitro, cyano, formyl or optionally substituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy,aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl,aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; one or both of R⁵ andR⁶ may represent an oxo group when attached to a carbon atom; R⁵ and R⁶when attached to nitrogen atom represents hydrogen, hydroxy, formyl oroptionally substituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl,acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino,aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy,heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid derivatives, or sulfonic acid derivatives; X representsa heteroatom selected from oxygen, sulfur or NR¹¹ where R¹¹ is selectedfrom hydrogen, or optionally substituted alkyl, cycloalkyl, aryl,aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonylgroups; Ar represents an optionally substituted divalent single or fusedaromatic or heterocyclic group; R⁷ represents hydrogen atom, hydroxy,alkoxy, halogen, lower alkyl, or optionally substituted aralkyl group;R⁸ represents hydrogen; hydroxy, alkoxy, halogen, lower alkyl group,acyl, or optionally substituted aralkyl; R⁹ represents hydrogen, oroptionally substituted groups selected from alkyl, cycloalkyl, aryl,aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl,or heteroaralkyl groups; the linking group represented by-(CH₂)_(n)-(O)_(m)- may be attached either through a nitrogen atom or acarbon atom; n is an integer ranging from 1-4 and m is an integer 0or
 1. 13. A process for the preparation of compound of formula (IVf)described in claim 12 where R⁷ and R⁸ represent hydrogen atoms and allother symbols are as defined in claim 12 which comprises: a) reacting acompound of formula (IIIa)

where all symbols are as defined above with a compound of formula (IVh)R⁹OCH₂P⁺PPh₃ ⁻Hal (IVh) where R⁹ represents optionally substitutedgroups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl,alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl,acyl, heterocyclyl, heteroaryl, or heteroaralkyl groups and Halrepresents a halogen atom, to yield a compound of formula (IVi)

where all symbols are as defined above, b) reacting a compound offormula (IVi) with an alcohol of the formula R⁹OH where R⁹ is as definedabove to yield a compound of formula (IVj),

where are all symbols are as defined above, c) reacting a compound offormula (IVj) obtained above where all symbols are as defined above withtrialkylsilyl cyanide to produce a compound of formula (IVf) where allsymbols are as defined above.
 14. An intermediate of formula (IVg)

where the groups R¹, R², R³, R⁴, and the groups R⁵ and R⁶ when attachedto a carbon atom, may be same or different and represent hydrogen,halogen, hydroxy, nitro, cyano, formyl or optionally substituted groupsselected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy,aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl,heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl,aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino,aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or itsderivatives, or sulfonic acid or its derivatives; one or both of R⁵ andR⁶ may represent an oxo group when attached to a carbon atom; R⁵ and R⁶when attached to a nitrogen atom represents hydrogen, hydroxy, formyl oroptionally substituted groups selected from alkyl, cycloalkyl, alkoxy,cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl,acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino,aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy,heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups,carboxylic acid derivatives, or sulfonic acid derivatives; X representsa heteroatom selected from oxygen, sulfur or NR¹¹ where R¹¹ is selectedfrom hydrogen, or optionally substituted alkyl, cycloalkyl, aryl,aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonylgroups; Ar represents an optionally substituted divalent single or fusedaromatic or heterocyclic group; R⁷ represents hydrogen atom, hydroxy,alkoxy, halogen, lower alkyl, or optionally substituted aralkyl group;R¹⁰ represents hydrogen or optionally substituted groups selected fromalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, orheteroaralkyl groups; Y represents oxygen; the linking group representedby -(CH₂)_(n)-(O)_(m)- may be attached either through a nitrogen atom ora carbon atom; n is an integer ranging from 1-4 and m is an integer 0or
 1. 15. A process for the preparation of compound of formula (IVg)described in claim 14, which comprises: a) reacting a compound offormula (IIIh)

where L¹ is a leaving group and all other symbols are as defined inclaim 14 with a compound of formula (IVl)

where R⁸ is a hydrogen atom and all other symbols are as defined inclaim 14, to yield a compound of formula (IVk)

where R⁸ is a hydrogen atom and all other symbols are as defined above,b) reacting a compound of formula (IVk) obtained above with adiazotizing agent.
 16. A compound according to claim 1 which is selectedfrom: Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;(±) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(+) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(−) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;Ethyl(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropenoate;Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;(±) Methyl3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate;(+) Methyl3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate;(−) Methyl3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoate;(±)Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(+)Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(−)Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(±) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(+) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(−) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(±) Methyl2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(+) Methyl2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(−) Methyl2-(2-fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;Ethyl(E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropenoate;(±) Methyl3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(+) Methyl3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(−) Methyl3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;Ethyl(E/Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropenoate;(±) Methyl3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate;(+) Methyl3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate;(−) Methyl3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoate;Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;Ethyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoate;Ethyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoate;Ethyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoate; Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate;(±) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;(+) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;(−) Methyl3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropenoate;(±) Methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;(+) Methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;(−) Methyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;Ethyl(E/Z)-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate;(±) Methyl3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;(+) Methyl3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;(−) Methyl3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;Ethyl(E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropenoate;(±) Methyl3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;(+) Methyl3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;(−) Methyl3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;(±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (±)3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts; (+)3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts; (−)3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts; (±)3-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts; (+)3-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts; (−)3-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanoicacid and its salts; (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (+)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (−)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(+) 3-[4-[2-(2,3-Dihydro1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide; (−)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(±)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(+)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(−)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(±)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(+)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(−)N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(±)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(+)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(−)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(±)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(+)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;(−)N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanamide;2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts;2-(2-Fluorobenzyl)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (±)3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (+)3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (−)3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (±)3-[4-[2-(3-Oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (+)3-[4-[2-(3-Oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (−)3-[4-[2-(3-Oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoicacid and its salts; (±)3-[6-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts; (+)3-[6-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts; (−)3-[6-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts; (±)3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts; (+)3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts; (−)3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanoicacid and its salts; (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts; (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts; (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts; (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts; (+)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts; (−)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoicacid and its salts; (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoicacid and its salts; (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoicacid and its salts; (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropanoicacid and its salts; (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid and its salts; (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid and its salts; (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropanoicacid and its salts; (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid and its salts; (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid and its salts; (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxypropanoicacid and its salts; (±)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (+)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (−)3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (±)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (+)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (−)3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (±) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;(+) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;(−) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;(±)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (+)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (−)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (±) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;(+) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;(−) Methyl2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoate;(±)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (+)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (−)2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanoicacid and its salts; (±) 4-Nitrophenyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(+) 4-Nitrophenyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(−) 4-Nitrophenyl3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate;(±)3-[4-(4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoicacid and its salts; (+)3-[4-(4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoicacid and its salts; (−)3-[4-(4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoicacid and its salts; (±)4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;(+)4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate;and (−)4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanoate.17. A method of preventing or treating hypercholesteremia, obesity withbeneficial effects on hyperlipemia, hyperglycemia, osteoporosis,obesity, glucose intolerance, insulin resistance, or diseases in whichinsulin resistance is the underlying pathophysiological mechanismcomprising administering a compound of formula (I) as defined in claim 1to a patient in need thereof.
 18. A method according to claim 17,wherein the disease is type II diabetes, impaired glucose tolerance,dyslipidemia, disorders related to Syndrome X including hypertension,obesity, insulin resistance, atherosclerosis, hyperlipidemia, coronaryartery disease and other cardiovascular disorders; renal diseasesincluding glomerulonephritis, glomerulosclerosis, nephrotic syndrome,and hypertensive nephrosclerosis; psoriasis, polycystic ovarian syndrome(PCOS), dementia, diabetic complications and osteoporosis.
 19. Apharmaceutical composition which comprises a compound of formula (I)

as defined in claim 1 and a pharmaceutically acceptable carrier,diluent, excipient or solvate.
 20. A pharmaceutical composition asclaimed in claim 19, in the form of a tablet, capsule, powder, syrup,solution or suspension.
 21. A method of preventing or treatinghypercholesteremia, obesity with beneficial effects on hyperlipemia,hyperglycemia, osteoporosis, obesity, glucose intolerance, insulinresistance, or diseases in which insulin resistance is the underlyingpathophysiological mechanism comprising administering a compound offormula (I) as defined in claim 1, and a pharmaceutically acceptablecarrier, diluent, solvate or excipient to a patient in need thereof. 22.A method according to claim 21, wherein the disease is type II diabetes,impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX including hypertension, obesity, insulin resistance, atherosclerosis,hyperlipidemia, coronary artery disease and other cardiovasculardisorders; renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, or hypertensive nephrosclerosis;psoriasis, polycystic ovarian syndrome (PCOS), dementia, diabeticcomplications and osteoporosis.
 23. A method of reducing totalcholesterol, body weight, blood plasma glucose, triglycerides, LDL, VLDLand free fatty acids in the plasma comprising administering a compoundof formula (I), as defined in claim 1 and a pharmaceutically acceptablecarrier, diluent or solvates or excipient to a patient in need thereof.24. A pharmaceutical composition which comprises, a compound accordingto claim 16 as an active ingredient and a pharmaceutically acceptablecarrier, diluent or excipient.
 25. A pharmaceutical composition asclaimed in claim 24, in the form of a tablet, capsule, powder, syrup,solution or suspension.
 26. A method of preventing or treatinghypercholesteremia, obesity with beneficial effects on hyperlipemia,hyperglycemia, osteoporosis, obesity, glucose intolerance, insulinresistance, or diseases in which insulin resistance is the underlyingpathophysiological mechanism comprising administering a compound offormula (I) as defined in claim 16, and a pharmaceutically acceptablecarrier, diluent, solvate or excipient to a patient in need thereof. 27.A method according to claim 26, wherein the disease is type II diabetes,impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX selected from hypertension, obesity, insulin resistance,atherosclerosis, hyperlipidemia, coronary artery disease and othercardiovascular disorders; renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, and hypertensivenephrosclerosis, psoriasis, and polycystic ovarian syndrome (PCOS),dementia, diabetic complications and osteoporosis.
 28. A method ofreducing cholesterol, body weight, blood glucose, triglycerides, andfree fatty acids comprising administering a compound as defined in claim16 and a pharmaceutically acceptable carrier, diluent or solvates orexcipient to a patient in need thereof.